2022/11/02 更新

写真a

オウ ヒデマサ
王 英正
OH Hidemasa
所属
岡山大学病院 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 大阪大学 )

研究キーワード

  • 再生医学

  • 細胞療法

  • 心不全

  • 心筋細胞

  • 幹細胞

  • Cell Therapy

  • Cardiac Regeneration

  • Stem Cells

研究分野

  • ライフサイエンス / 循環器内科学

経歴

  • - Professor,University Hospital of Medicine and Dentistry,Okayama University

    2010年

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  • - 岡山大学岡山大学病院 教授

    2010年

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  • Associate Professor,University Hospital of Medicine and Dentistry,Okayama University

    2009年 - 2010年

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  • 岡山大学   Okayama University Hospital

    2009年 - 2010年

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  • Associate Professor

    2008年 - 2009年

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  • 京都府立医科大学

    2008年 - 2009年

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  • 京都大学付属病院 准教授

    2003年 - 2008年

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  • Associate Professor

    2003年 - 2008年

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  • Baylor College of Medicine   Assistant Professor

    2002年7月 - 2003年8月

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    国名:アメリカ合衆国

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▼全件表示

委員歴

  • 特定認定再生医療等委員会   委員  

    2017年4月 - 現在   

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論文

  • Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy. 国際誌

    Kenta Hirai, Daiki Ousaka, Yosuke Fukushima, Maiko Kondo, Takahiro Eitoku, Yusuke Shigemitsu, Mayuko Hara, Kenji Baba, Tatsuo Iwasaki, Shingo Kasahara, Shinichi Ohtsuki, Hidemasa Oh

    Science translational medicine   12 ( 573 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)-mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

    DOI: 10.1126/scitranslmed.abb3336

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  • 新しい手術方法の開発「治療から再生へ-再生医療の進歩」 小児心不全に対する再生医療のUpdate

    平井 健太, 大月 審一, 馬場 健児, 近藤 麻衣子, 栄徳 隆裕, 福嶋 遥佑, 重光 祐輔, 原 真祐子, 笠原 真悟, 王 英正

    日本小児循環器学会雑誌   36 ( Suppl.2 )   s2 - 114   2020年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • ラット下大静脈絞扼術モデルを用いた下半身うっ血負荷が心肺に与える影響解析 フォンタン循環の病態解明に向けて

    逢坂 大樹, 後藤 拓弥, 平井 健太, 笠原 真悟, 王 英正

    日本小児循環器学会雑誌   35 ( Suppl.1 )   s1 - 382   2019年6月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • ラットを用いた心臓内幹細胞経静脈投与後の血行動態および安全性評価

    後藤 拓弥, 逢坂 大樹, 平井 健太, 笠原 真悟, 王 英正

    日本小児循環器学会雑誌   35 ( Suppl.1 )   s1 - 170   2019年6月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • ラット下大静脈絞扼術による下半身うっ血負荷が心肺に与える影響およびhemodynamic preconditioningの効果検証 フォンタン循環への応用にむけて

    逢坂 大樹, 後藤 拓弥, 平井 健太, 笠原 真悟, 王 英正

    日本循環器学会学術集会抄録集   83回   CP32 - 7   2019年3月

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    記述言語:日本語   出版者・発行元:(一社)日本循環器学会  

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  • Impact of Cardiac Progenitor Cells on Heart Failure and Survival in Single Ventricle Congenital Heart Disease. 国際誌

    Toshikazu Sano, Daiki Ousaka, Takuya Goto, Shuta Ishigami, Kenta Hirai, Shingo Kasahara, Shinichi Ohtsuki, Shunji Sano, Hidemasa Oh

    Circulation research   122 ( 7 )   994 - 1005   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RATIONALE: Intracoronary administration of cardiosphere-derived cells (CDCs) in patients with single ventricles resulted in a short-term improvement in cardiac function. OBJECTIVE: To test the hypothesis that CDC infusion is associated with improved cardiac function and reduced mortality in patients with heart failure. METHODS AND RESULTS: We evaluated the effectiveness of CDCs using an integrated cohort study in 101 patients with single ventricles, including 41 patients who received CDC infusion and 60 controls treated with staged palliation alone. Heart failure with preserved ejection fraction (EF) or reduced EF was stratified by the cardiac function after surgical reconstruction. The main outcome measure was to evaluate the magnitude of improvement in cardiac function and all-cause mortality at 2 years. Animal studies were conducted to clarify the underlying mechanisms of heart failure with preserved EF and heart failure with reduced EF phenotypes. At 2 years, CDC infusion increased ventricular function (stage 2: +8.4±10.0% versus +1.6±6.4%, P=0.03; stage 3: +7.9±7.5% versus -1.1±5.5%, P<0.001) compared with controls. In all available follow-up data, survival did not differ between the 2 groups (log-rank P=0.225), whereas overall patients treated by CDCs had lower incidences of late failure (P=0.022), adverse events (P=0.013), and catheter intervention (P=0.005) compared with controls. CDC infusion was associated with a lower risk of adverse events (hazard ratio, 0.411; 95% CI, 0.179-0.942; P=0.036). Notably, CDC infusion reduced mortality (P=0.038) and late complications (P<0.05) in patients with heart failure with reduced EF but not with heart failure with preserved EF. CDC-treated rats significantly reversed myocardial fibrosis with differential collagen deposition and inflammatory responses between the heart failure phenotypes. CONCLUSIONS: CDC administration in patients with single ventricles showed favorable effects on ventricular function and was associated with reduced late complications except for all-cause mortality after staged procedures. Patients with heart failure with reduced EF but not heart failure with preserved EF treated by CDCs resulted in significant improvement in clinical outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01273857 and NCT01829750.

    DOI: 10.1161/CIRCRESAHA.117.312311

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  • Transcoronary cell infusion with the stop-flow technique in children with single-ventricle physiology. 国際誌

    Takahiro Eitoku, Kenji Baba, Maiko Kondou, Yoshihiko Kurita, Yousuke Fukushima, Kenta Hirai, Shinichi Ohtsuki, Shuta Ishigami, Shunji Sano, Hidemasa Oh

    Pediatrics international : official journal of the Japan Pediatric Society   60 ( 3 )   240 - 246   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Almost all reports on cardiac regeneration therapy have referred to adults, and only a few have focused on transcoronary infusion of cardiac progenitor cells using the stop-flow technique in children. METHODS: Intracoronary autologous cardiosphere-derived cell (CDC) transfer was conducted at Okayama University as a phase 1 clinical trial for seven patients with hypoplastic left heart syndrome between January 2011 and December 2012, and as a phase 2 clinical trial for 34 patients with single-ventricle physiology between July 2013 and March 2015. RESULTS: A total of 41 patients with single-ventricle physiology underwent transcoronary infusion of CDC with the stop-flow technique. The median age was 33 months (range, 5-70 months) and the median weight was 10.1 kg (range, 4.1-16.0 kg). Transient adverse events occurred during the procedure, including ST-segment elevation or depression, hypotension, bradycardia, and coronary artery vasospasm. All patients completely recovered. There were no major procedure-related adverse events. In this study, transcoronary infusion of CDC using the stop-flow technique was successfully completed in all patients. CONCLUSION: Transcoronary infusion of CDC using the stop-flow technique in children is a feasible and safe procedure.

    DOI: 10.1111/ped.13485

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  • 小児循環器領域におけるiPS細胞研究の展望 単心室症における自己心臓内幹細胞治療の臨床と先天性心疾患におけるiPS細胞の研究の現況と展望

    新井 禎彦, 石神 修大, 小林 純子, 後藤 拓弥, 佐野 俊和, 大月 審一, 王 英正, 小谷 恭弘, 黒子 洋介, 笠原 真悟, 佐野 俊二

    日本小児循環器学会雑誌   33 ( Suppl.1 )   s1 - 126   2017年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • Cell Therapy Trials in Congenital Heart Disease. 国際誌

    Hidemasa Oh

    Circulation research   120 ( 8 )   1353 - 1366   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dramatic evolution in medical and catheter interventions and complex surgeries to treat children with congenital heart disease (CHD) has led to a growing number of patients with a multitude of long-term complications associated with morbidity and mortality. Heart failure in patients with hypoplastic left heart syndrome predicated by functional single ventricle lesions is associated with an increase in CHD prevalence and remains a significant challenge. Pathophysiological mechanisms contributing to the progression of CHD, including single ventricle lesions and dilated cardiomyopathy, and adult heart disease may inevitably differ. Although therapeutic options for advanced cardiac failure are restricted to heart transplantation or mechanical circulatory support, there is a strong impetus to develop novel therapeutic strategies. As lower vertebrates, such as the newt and zebrafish, have a remarkable ability to replace lost cardiac tissue, this intrinsic self-repair machinery at the early postnatal stage in mice was confirmed by partial ventricular resection. Although the underlying mechanistic insights might differ among the species, mammalian heart regeneration occurs even in humans, with the highest degree occurring in early childhood and gradually declining with age in adulthood, suggesting the advantage of stem cell therapy to ameliorate ventricular dysfunction in patients with CHD. Although effective clinical translation by a variety of stem cells in adult heart disease remains inconclusive with respect to the improvement of cardiac function, case reports and clinical trials based on stem cell therapies in patients with CHD may be invaluable for the next stage of therapeutic development. Dissecting the differential mechanisms underlying progressive ventricular dysfunction in children and adults may lead us to identify a novel regenerative therapy. Future regenerative technologies to treat patients with CHD are exciting prospects for heart regeneration in general practice.

    DOI: 10.1161/CIRCRESAHA.117.309697

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  • Intracoronary Cardiac Progenitor Cells in Single Ventricle Physiology: The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) Randomized Phase 2 Trial. 国際誌

    Shuta Ishigami, Shinichi Ohtsuki, Takahiro Eitoku, Daiki Ousaka, Maiko Kondo, Yoshihiko Kurita, Kenta Hirai, Yosuke Fukushima, Kenji Baba, Takuya Goto, Naohiro Horio, Junko Kobayashi, Yosuke Kuroko, Yasuhiro Kotani, Sadahiko Arai, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    Circulation research   120 ( 7 )   1162 - 1173   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RATIONALE: Patients with single ventricle physiology are at high risk of mortality resulting from ventricular dysfunction. The preliminary results of the phase 1 trial showed that cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. OBJECTIVE: To determine whether intracoronary delivery of autologous CDCs improves cardiac function in patients with single ventricle physiology. METHODS AND RESULTS: We conducted a phase 2 randomized controlled study to assign in a 1:1 ratio 41 patients who had single ventricle physiology undergoing stage 2 or 3 palliation to receive intracoronary infusion of CDCs 4 to 9 weeks after surgery or staged reconstruction alone (study A). The primary outcome measure was to assess improvement in cardiac function at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC infusion on request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in the controls (+6.4% [SD, 5.5] versus +1.3% [SD, 3.7]; P=0.003). In study B, a late CDC infusion in 17 controls increased the ventricular function at 3 months compared with that at baseline (38.8% [SD, 7.7] versus 34.8% [SD, 7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD, 6.6] versus 35.0% [SD, 8.2]; P<0.0001) and volumes (P<0.001), somatic growth (P<0.0001) with increased trophic factors production, such as insulin-like growth factor-1 and hepatocyte growth factor, and quality of life, along with a reduced heart failure status (P<0.0001) and cardiac fibrosis (P=0.014) relative to baseline. CONCLUSIONS: Intracoronary infusion of CDCs after staged palliation favorably affected cardiac function by reverse remodeling in patients with single ventricle physiology. This impact may improve heart failure status, somatic growth, and quality of life in patients and reduce parenting stress for their families. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

    DOI: 10.1161/CIRCRESAHA.116.310253

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  • Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases. 国際誌

    Hidemasa Oh, Hiroshi Ito, Shunji Sano

    Journal of cardiology   68 ( 5 )   361 - 367   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases.

    DOI: 10.1016/j.jjcc.2016.04.010

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  • Dissecting the Left Heart Hypoplasia by Pluripotent Stem Cells

    Junko Kobayashi, Shunji Sano, Hidemasa Oh

    337 - 339   2016年

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    記述言語:英語   出版者・発行元:Springer  

    The genetic background of hypoplastic left heart syndrome (HLHS) is still unknown. Cardiac differentiation from pluripotent stem cells (PSCs) can recapitulate the cardiogenesis in vitro, and PSC technology could be useful to dissect the diseases with the complex mechanisms. In the past few years, some researches were reported to seek the pathogenesis of HLHS by using PSCs. This paper reports the achievements.

    DOI: 10.1007/978-4-431-54628-3

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  • Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial. 国際誌

    Suguru Tarui, Shuta Ishigami, Daiki Ousaka, Shingo Kasahara, Shinichi Ohtsuki, Shunji Sano, Hidemasa Oh

    The Journal of thoracic and cardiovascular surgery   150 ( 5 )   1198 - 1207   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Our aim was to assess midterm safety and clinical outcomes of intracoronary infusion of cardiosphere-derived cells (CDCs) after staged palliation in patients with hypoplastic left heart syndrome (HLHS). METHODS: In this prospective, controlled study, 14 consecutive patients with HLHS who were undergoing 2- or 3-stage surgical palliations were assigned to receive intracoronary CDC infusion 1 month after cardiac surgery (n = 7), followed by 7 patients allocated to a control group with standard care alone. The primary end point was to assess procedural feasibility and safety; the secondary end point was to evaluate cardiac function and heart failure status through 36-month follow-up. RESULTS: No complications, including tumor formation, were reported within 36 months after CDC infusion. Echocardiography showed significantly greater improvement in right ventricular ejection fraction (RVEF) in infants receiving CDCs than in controls at 36 months (+8.0% ± 4.7% vs +2.2% ± 4.3%; P = .03). These cardiac function improvements resulted in reduced brain natriuretic peptide levels (P = .04), lower incidence of unplanned catheter interventions (P = .04), and higher weight-for-age z score (P = .02) at 36 months relative to controls. As independent predictors of treatment responsiveness, absolute changes in RVEF at 36 months were negatively correlated with age, weight-for-age z score, and RVEF at CDC infusion. CONCLUSIONS: Intracoronary CDC infusion after staged procedure in patients with HLHS is safe and improves RVEF, which persists during 36-month follow-up. This therapeutic strategy may enhance somatic growth and reduce incidence of heart failure.

    DOI: 10.1016/j.jtcvs.2015.06.076

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  • 小児循環器領域と女性医師 出産後も心臓血管外科研修を継続するための要件とは何か 育児中に学位取得、心臓血管外科研修をして考えたこと

    小林 純子, 樽井 俊, 藤井 泰宏, 小谷 恭弘, 川畑 拓也, 黒子 洋介, 吉積 功, 新井 禎彦, 笠原 真悟, 王 英正, 佐野 俊二

    日本小児循環器学会雑誌   31 ( Suppl.1 )   s1 - 134   2015年7月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • 左心低形成症候群に対する心臓内幹細胞自家移植療法 第I相臨床試験(TICAP trial)18ヵ月長期成績

    石神 修大, 樽井 俊, 後藤 拓弥, 奥山 倫弘, 逢坂 大樹, 小林 純子, 藤井 泰宏, 黒子 洋介, 川畑 拓也, 小谷 泰弘, 新井 禎彦, 笠原 真悟, 佐野 俊二, 王 英正

    日本心臓血管外科学会雑誌   44 ( 3 )   viii - xii   2015年5月

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    記述言語:日本語   出版者・発行元:(NPO)日本心臓血管外科学会  

    左心低形成症候群14例を対象とした心臓内幹細胞自家移植療法の第I相臨床試験の結果を報告した。移植群7例においては両方向グレン手術あるいはフォンタン手術時に、右心房から採取した心臓組織から幹細胞を分離培養し、術後1ヵ月で30万個/kgの心筋幹細胞の選択的冠動脈内注入を行った。移植群で幹細胞注入に伴う心筋逸脱酵素の上昇はなく、心筋虚血症などの合併症もなかった。心臓超音波で評価した移植群の右室駆出率は、移植後3ヵ月から有意な改善を認め、18ヵ月時点では移植前と比較して平均+7.1%と効果が持続した。一方非移植群7例では+2.1%の改善にとどまり、細胞治療による改善効果が示された。またカテーテル検査値に基づく評価では、移植群で心筋弾性能やポンプ機能の改善を認め、心不全症状も著明に改善し、成長障害に対する有意な成長促進がみられた。非移植群では心不全症状の軽減や身体成長の改善は観察されなかった。

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  • Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. 国際誌

    Shuta Ishigami, Shinichi Ohtsuki, Suguru Tarui, Daiki Ousaka, Takahiro Eitoku, Maiko Kondo, Michihiro Okuyama, Junko Kobayashi, Kenji Baba, Sadahiko Arai, Takuya Kawabata, Ko Yoshizumi, Atsushi Tateishi, Yosuke Kuroko, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    Circulation research   116 ( 4 )   653 - 64   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RATIONALE: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. OBJECTIVE: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. METHODS AND RESULTS: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01273857.

    DOI: 10.1161/CIRCRESAHA.116.304671

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  • 左心低形成症候群に対する心臓内幹細胞自家移植療法 第I相臨床試験18ヵ月長期成績

    石神 修大, 樽井 俊, 逢坂 大樹, 後藤 拓弥, 奥山 倫弘, 小林 純子, 藤井 泰宏, 黒子 洋介, 川畑 拓也, 小谷 恭弘, 吉積 功, 新井 禎彦, 笠原 真悟, 佐野 俊二, 王 英正

    日本心臓血管外科学会雑誌   44 ( Suppl. )   185 - 185   2015年1月

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    記述言語:日本語   出版者・発行元:(NPO)日本心臓血管外科学会  

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  • MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors. 国際誌

    Takehiro Ogata, Daisuke Naito, Naohiko Nakanishi, Yukiko K Hayashi, Takuya Taniguchi, Kotaro Miyagawa, Tetsuro Hamaoka, Naoki Maruyama, Satoaki Matoba, Koji Ikeda, Hiroyuki Yamada, Hidemasa Oh, Tomomi Ueyama

    Proceedings of the National Academy of Sciences of the United States of America   111 ( 10 )   3811 - 6   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as "caveolae." Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR-induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.

    DOI: 10.1073/pnas.1315359111

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  • Directed differentiation of patient-specific induced pluripotent stem cells identifies the transcriptional repression and epigenetic modification of NKX2-5, HAND1, and NOTCH1 in hypoplastic left heart syndrome. 国際誌

    Junko Kobayashi, Masashi Yoshida, Suguru Tarui, Masataka Hirata, Yusuke Nagai, Shingo Kasahara, Keiji Naruse, Hiroshi Ito, Shunji Sano, Hidemasa Oh

    PloS one   9 ( 7 )   e102796   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS.

    DOI: 10.1371/journal.pone.0102796

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  • 疾患特異的iPS細胞を用いた左心低形成症候群における心臓発生異常の解明

    小林 純子, 樽井 俊, 平田 昌敬, 川畑 拓也, 黒子 洋介, 立石 篤史, 吉積 功, 新井 禎彦, 笠原 真悟, 佐野 俊二, 王 英正

    日本外科学会雑誌   114 ( 臨増2 )   415 - 415   2013年3月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 先天性心疾患の疾患特異的iPS細胞の樹立と左心低形成症候群の心臓発生異常の解明

    小林 純子, 樽井 俊, 平田 昌敬, 川畑 拓也, 黒子 洋介, 立石 篤史, 吉積 功, 新井 禎彦, 笠原 真悟, 佐野 俊二, 王 英正

    日本心臓血管外科学会雑誌   42 ( Suppl. )   274 - 274   2013年2月

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    記述言語:日本語   出版者・発行元:(NPO)日本心臓血管外科学会  

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  • 先天性心疾患患者由来の心臓内幹細胞を用いた疾患特異的ヒトiPS細胞の樹立と機能解析

    小林 純子, 樽井 俊, 平田 昌敬, 川畑 拓也, 黒子 洋介, 立石 篤史, 吉積 功, 新井 禎彦, 笠原 真悟, 佐野 俊二, 王 英正

    日本小児循環器学会雑誌   28 ( Suppl. )   s145 - s145   2012年6月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy. 国際誌

    Gabriela Rodriguez, Tomomi Ueyama, Takehiro Ogata, Grazyna Czernuszewicz, Yanli Tan, Gerald W Dorn 2nd, Roberta Bogaev, Katsuya Amano, Hidemasa Oh, Hiroaki Matsubara, James T Willerson, Ali J Marian

    Circulation. Cardiovascular genetics   4 ( 4 )   349 - 58   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. METHODS AND RESULTS: We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ(2)=8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC. CONCLUSIONS: MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.

    DOI: 10.1161/CIRCGENETICS.111.959866

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  • PARM-1 is an endoplasmic reticulum molecule involved in endoplasmic reticulum stress-induced apoptosis in rat cardiac myocytes. 国際誌

    Koji Isodono, Tomosaburo Takahashi, Hiroko Imoto, Naohiko Nakanishi, Takehiro Ogata, Satoshi Asada, Atsuo Adachi, Tomomi Ueyama, Hidemasa Oh, Hiroaki Matsubara

    PloS one   5 ( 3 )   e9746   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To identify novel transmembrane and secretory molecules expressed in cardiac myocytes, signal sequence trap screening was performed in rat neonatal cardiac myocytes. One of the molecules identified was a transmembrane protein, prostatic androgen repressed message-1 (PARM-1). While PARM-1 has been identified as a gene induced in prostate in response to castration, its function is largely unknown. Our expression analysis revealed that PARM-1 was specifically expressed in hearts and skeletal muscles, and in the heart, cardiac myocytes, but not non-myocytes expressed PARM-1. Immunofluorescent staining showed that PARM-1 was predominantly localized in endoplasmic reticulum (ER). In Dahl salt-sensitive rats, high-salt diet resulted in hypertension, cardiac hypertrophy and subsequent heart failure, and significantly stimulated PARM-1 expression in the hearts, with a concomitant increase in ER stress markers such as GRP78 and CHOP. In cultured cardiac myocytes, PARM-1 expression was stimulated by proinflammatory cytokines, but not by hypertrophic stimuli. A marked increase in PARM-1 expression was observed in response to ER stress inducers such as thapsigargin and tunicamycin, which also induced apoptotic cell death. Silencing PARM-1 expression by siRNAs enhanced apoptotic response in cardiac myocytes to ER stresses. PARM-1 silencing also repressed expression of PERK and ATF6, and augmented expression of CHOP without affecting IRE-1 expression and JNK and Caspase-12 activation. Thus, PARM-1 expression is induced by ER stress, which plays a protective role in cardiac myocytes through regulating PERK, ATF6 and CHOP expression. These results suggested that PARM-1 is a novel ER transmembrane molecule involved in cardiac remodeling in hypertensive heart disease.

    DOI: 10.1371/journal.pone.0009746

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  • Stem cell engineering for cardiac tissue regeneration. 国際誌

    Masashi Yoshida, Hidemasa Oh

    Cardiology   115 ( 3 )   191 - 3   2010年

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    記述言語:英語  

    DOI: 10.1159/000281839

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  • Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload. 国際誌

    Seimi Satomi-Kobayashi, Tomomi Ueyama, Steffen Mueller, Ryuji Toh, Tomoya Masano, Tsuyoshi Sakoda, Yoshiyuki Rikitake, Jun Miyoshi, Hiroaki Matsubara, Hidemasa Oh, Seinosuke Kawashima, Ken-ichi Hirata, Yoshimi Takai

    Hypertension (Dallas, Tex. : 1979)   54 ( 4 )   825 - 31   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca(2+)-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload-induced cardiac dysfunction.

    DOI: 10.1161/HYPERTENSIONAHA.109.130443

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  • Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction. 国際誌

    Naofumi Takehara, Yoshiaki Tsutsumi, Kento Tateishi, Takehiro Ogata, Hideo Tanaka, Tomomi Ueyama, Tomosaburo Takahashi, Tetsuro Takamatsu, Masanori Fukushima, Masashi Komeda, Masaaki Yamagishi, Hitoshi Yaku, Yasuhiko Tabata, Hiroaki Matsubara, Hidemasa Oh

    Journal of the American College of Cardiology   52 ( 23 )   1858 - 1865   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: This study was designed to determine whether controlled release of basic fibroblast growth factor (bFGF) might improve human cardiosphere-derived cell (hCDC) therapy in a pig model of chronic myocardial infarction. BACKGROUND: Current cell therapies for cardiac repair are limited by loss of the transplanted cells and poor differentiation. METHODS: We conducted 2 randomized, placebo-controlled studies in immunosuppressed pigs with anterior myocardial infarctions. Four weeks after coronary reperfusion, 14 pigs were randomly assigned to receive an intramyocardial injection of placebo medium with or without bFGF-incorporating hydrogel implantation. As a second study, 26 pigs were randomized to receive controlled release of bFGF combined with or without hCDCs or bone marrow-derived mesenchymal stem cell transplantation 4 weeks after reperfusion. RESULTS: Controlled release of bFGF in ischemic myocardium significantly augmented the formation of microvascular networks to enhance myocardial perfusion and contractile function. When combined with cell transplantation, the additive effects of bFGF were confined to hCDC-injected animals, but were not observed in animals receiving human bone marrow-derived mesenchymal stem cell transplantation. This was shown by increased donor-cell engraftment and enhanced cardiomyocyte differentiation in the transplanted hearts, resulting in synergistically improved ventricular function and regional wall motion and reduced infarct size. CONCLUSIONS: Controlled delivery of bFGF modulates the post-ischemic microenvironment to enhance hCDC engraftment and differentiation. This novel strategy demonstrates significant functional improvements after myocardial infarction and may potentially represent a therapeutic approach to be studied in a clinical trial in human heart failure.

    DOI: 10.1016/j.jacc.2008.06.052

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  • Stemming heart failure with cardiac- or reprogrammed-stem cells. 国際誌

    Kento Tateishi, Naofumi Takehara, Hiroaki Matsubara, Hidemasa Oh

    Journal of cellular and molecular medicine   12 ( 6A )   2217 - 32   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Despite extensive efforts to control myocyte growth by genetic targeting of the cell cycle machinery and small molecules for cardiac repair, adult myocytes themselves appeared to divide a limited number of times in response to a variety of cardiac muscle stresses. Rare tissue-resident stem cells are thought to exist in many adult organs that are capable of self-renewal and differentiation and possess a range of actions that are potentially therapeutic. Recent studies suggest that a population of cardiac stem cells (CSCs) is maintained after cardiac development in the adult heart in mammals including human beings; however, homeostatic cardiomyocyte replacement might be stem cell-dependent, and functional myocardial regeneration after cardiac muscle damage is not yet considered as sufficient to fully maintain or reconstitute the cardiovascular system and function. Although it is clear that adult CSCs have limitations in their capabilities to proliferate extensively and differentiate in response to injury in vivo for replenishing mature car-diomyocytes and potentially function as resident stem cells. Transplantation of CSCs expanded ex vivo seems to require an integrated strategy of cell growth-enhancing factor(s) and tissue engineering technologies to support the donor cell survival and subsequent proliferation and differentiation in the host microenvironment. There has been substantial interest regarding the evidence that mammalian fibroblasts can be genetically reprogrammed to induced pluripotent stem (iPS) cells, which closely resemble embryonic stem (ES) cell properties capable of differentiating into functional cardiomyocytes, and these cells may provide an alternative cell source for generating patient-specific CSCs for therapeutic applications.

    DOI: 10.1111/j.1582-4934.2008.00487.x

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  • Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis. 国際誌

    Satoshi Asada, Tomosaburo Takahashi, Koji Isodono, Atsuo Adachi, Hiroko Imoto, Takehiro Ogata, Tomomi Ueyama, Hiroaki Matsubara, Hidemasa Oh

    American journal of physiology. Heart and circulatory physiology   295 ( 6 )   H2512-21   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although the modulated expression of Dicer is documented upon neoplastic transformation, little is known of the regulation of Dicer expression by environmental stimuli and its roles in the regulation of cellular functions in primary cells. In this study, we found that Dicer expression was downregulated upon serum withdrawal in human umbilical vein endothelial cells (HUVECs). Serum withdrawal induced a time-dependent repression of Dicer expression, which was specifically rescued by vascular endothelial cell growth factor or sphingosine-1-phosphate. When Dicer expression was silenced by short-hairpin RNA against Dicer, the cells were more prone to apoptosis under serum withdrawal, whereas the rate of apoptosis was comparable with control cells in the serum-containing condition. Real-time PCR-based gene expression profiling identified several genes, the expression of which was modulated by Dicer silencing, including adhesion and matrix-related molecules, caspase-3, and nitric oxide synthase 3 (NOS3). Dicer silencing markedly impaired migratory functions without affecting cell adhesion and repressed phosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 in adherent HUVECs. Dicer knockdown upregulated caspase-3 and downregulated NOS3 expression, and serum withdrawal indeed increased caspase-3 and decreased NOS3 expression. Furthermore, the overexpression of Dicer in HUVECs resulted in a marked reduction in apoptosis upon serum withdrawal and a decreased caspase-3 and increased NOS3 expression. The inhibition of NOS activity by Nomega-nitro-L-arginine methyl ester abrogated the effect of Dicer overexpression to rescue the cells from serum withdrawal-induced apoptosis. These results indicated that serum withdrawal decreases Dicer expression, leading to an increased susceptibility to apoptosis through the regulation of caspase-3 and NOS3 expression.

    DOI: 10.1152/ajpheart.00233.2008

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  • Crossveinless-2 controls bone morphogenetic protein signaling during early cardiomyocyte differentiation in P19 cells. 国際誌

    Koichiro Harada, Akiko Ogai, Tomosaburo Takahashi, Masafumi Kitakaze, Hiroaki Matsubara, Hidemasa Oh

    The Journal of biological chemistry   283 ( 39 )   26705 - 13   2008年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Increasing evidence indicates that bone morphogenetic proteins (BMPs) are crucial for cardiac induction, specification, and development. Although signaling of BMPs is tightly regulated through soluble BMP-binding proteins, how they regulate BMP signaling during cardiac differentiation remains unknown. To identify molecules responsible for BMP signaling during early cardiomyocyte differentiation of P19 cells, cDNA subtraction was performed. We found a bimodal expression of the BMP-binding protein Crossveinless-2 (Cv2) during cardiomyocyte differentiation; Cv2 is temporally expressed earlier than cardiac transcription factors such as Nkx2.5 and Tbx5 and acts as a suppressor for BMP signaling in P19 cells. We established a P19 clonal cell line harboring a cardiac alpha-myosin heavy chain promoter-driven enhanced green fluorescent protein gene to monitor cardiac differentiation by flow cytometry. Treatment with BMP2 during the first 2 days of differentiation suppressed cardiomyocyte differentiation through activation of down-stream targets Smad1/5/8 protein and Id1 gene, whereas treatment with Cv2 conversely inhibited Smad1/5/8 activation and Id1 expression, leading to increased generation of cardiac cells. RNA interference-mediated knockdown (KD) of endogenous Cv2 showed increased Smad1/5/8 activation and impaired cardiomyocyte differentiation. Expression of cardiac mesoderm markers was reduced, whereas expression of Id1 and endoderm markers such as Sox7, Hnf4, and E-cadherin was induced in Cv2-kinase dead cells. These phenotypes were rescued by the addition of Cv2 protein to the culture media during the first 2 days of differentiation or co-culture with parental cells. These data suggest that Cv2 may specify cardiac mesodermal lineage through inhibition of BMP signaling at early stage of cardiogenesis.

    DOI: 10.1074/jbc.M801485200

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  • MURC, a muscle-restricted coiled-coil protein, is involved in the regulation of skeletal myogenesis. 国際誌

    Masashi Tagawa, Tomomi Ueyama, Takehiro Ogata, Naofumi Takehara, Norio Nakajima, Koji Isodono, Satoshi Asada, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    American journal of physiology. Cell physiology   295 ( 2 )   C490-8   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Skeletal myogenesis is a multistep process by which multinucleated mature muscle fibers are formed from undifferentiated, mononucleated myoblasts. However, the molecular mechanisms of skeletal myogenesis have not been fully elucidated. Here, we identified muscle-restricted coiled-coil (MURC) protein as a positive regulator of myogenesis. In skeletal muscle, MURC was localized to the cytoplasm with accumulation in the Z-disc of the sarcomere. In C2C12 myoblasts, MURC expression occurred coincidentally with myogenin expression and preceded sarcomeric myosin expression during differentiation into myotubes. RNA interference (RNAi)-mediated knockdown of MURC impaired differentiation in C2C12 myoblasts, which was accompanied by impaired myogenin expression and ERK activation. Overexpression of MURC in C2C12 myoblasts resulted in the promotion of differentiation with enhanced myogenin expression and ERK activation during differentiation. During injury-induced muscle regeneration, MURC expression increased, and a higher abundance of MURC was observed in immature myofibers compared with mature myofibers. In addition, ERK was activated in regenerating tissue, and ERK activation was detected in MURC-expressing immature myofibers. These findings suggest that MURC is involved in the skeletal myogenesis that results from modulation of myogenin expression and ERK activation. MURC may play pivotal roles in the molecular mechanisms of skeletal myogenic differentiation.

    DOI: 10.1152/ajpcell.00188.2008

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  • MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance. 国際誌

    Takehiro Ogata, Tomomi Ueyama, Koji Isodono, Masashi Tagawa, Naofumi Takehara, Tsuneaki Kawashima, Koichiro Harada, Tomosaburo Takahashi, Tetsuo Shioi, Hiroaki Matsubara, Hidemasa Oh

    Molecular and cellular biology   28 ( 10 )   3424 - 36   2008年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.

    DOI: 10.1128/MCB.02186-07

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  • Skeletal muscle-derived progenitors capable of differentiating into cardiomyocytes proliferate through myostatin-independent TGF-beta family signaling. 国際誌

    Tetsuya Nomura, Tomomi Ueyama, Eishi Ashihara, Kento Tateishi, Satoshi Asada, Norio Nakajima, Koji Isodono, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    Biochemical and biophysical research communications   365 ( 4 )   863 - 9   2008年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The existence of skeletal muscle-derived stem cells (MDSCs) has been suggested in mammals; however, the signaling pathways controlling MDSC proliferation remain largely unknown. Here we report the isolation of myosphere-derived progenitor cells (MDPCs) that can give rise to beating cardiomyocytes from adult skeletal muscle. We identified that follistatin, an antagonist of TGF-beta family members, was predominantly expressed in MDPCs, whereas myostatin was mainly expressed in myogenic cells and mature skeletal muscle. Although follistatin enhanced the replicative growth of MDPCs through Smad2/3 inactivation and cell cycle progression, disruption of myostatin did not increase the MDPC proliferation. By contrast, inhibition of activin A (ActA) or growth differentiation factor 11 (GDF11) signaling dramatically increased MDPC proliferation via down-regulation of p21 and increases in the levels of cdk2/4 and cyclin D1. Thus, follistatin may be an effective progenitor-enhancing agent neutralizing ActA and GDF11 signaling to regulate the growth of MDPCs in skeletal muscle.

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  • Therapeutic potential of stem/progenitor cells in human skeletal muscle for cardiovascular regeneration. 国際誌

    Tetsuya Nomura, Eishi Ashihara, Kento Tateishi, Tomomi Ueyama, Tomosaburo Takahas-Hi, Masaaki Yamagishi, Toshikazu Kubo, Hitoshi Yaku, Hiroaki Matsubara, Hidemasa Oh

    Current stem cell research & therapy   2 ( 4 )   293 - 300   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although myoblast transplantation in patients with ischemic heart failure results in a significant improvement of cardiac function, subsequent studies have consistently shown the myotubes formation in the absence of electromechanical coupling with the neighboring host myocardium, accompanied with the short-term release of paracrine effectors from implanted cells. One major pitfall of using myoblasts is that transplanted cells do not differentiate into cardiomyocytes, which may cause the inherent proarrhythmogenic events. Therefore, whether a discrete subpopulation in heterogeneous muscle-cell cultures is responsible for substantial cardiovascular regeneration has yet to be investigated. We describe here the isolation of progenitor cells from human skeletal muscle. These cells proliferated as non-adherent myospheres in suspension and displayed early embryonic factors and mesenchymal cell-like characteristics. Flow cytometric analyses demonstrated that CD56/N-CAM/Leu-19, a neural cell adhesion molecule abundantly present in myoblasts, was absent in myospheres but was expressed in an adherent cell population containing myogenic precursors. Myosphere-derived progenitor cells (MDPCs) differentiated in culture to produce cardiac, smooth muscle, and endothelial cells. Transplantation of MDPCs into ischemic hearts in NOD/scid mice promoted angiogenesis with substantial cardiovascular regeneration. Our results provide a foundation to further study the cell and biological function of human MDPCs which may have potential therapeutic implications.

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  • Osteopontin is a myosphere-derived secretory molecule that promotes angiogenic progenitor cell proliferation through the phosphoinositide 3-kinase/Akt pathway. 国際誌

    Takehiro Ogata, Tomomi Ueyama, Tetsuya Nomura, Satoshi Asada, Masashi Tagawa, Tomoyuki Nakamura, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    Biochemical and biophysical research communications   359 ( 2 )   341 - 7   2007年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We have reported that skeletal myosphere-derived progenitor cells (MDPCs) can differentiate into vascular cells, and that MDPC transplantation into cardiomyopathic hearts improves cardiac function. However, the autocrine/paracrine molecules and underlying mechanisms responsible for MDPC growth have not yet been determined. To explore the molecules enhancing the proliferation of MDPCs, we performed serial analysis of gene expression and signal sequence trap methods using RNA isolated from MDPCs. We identified osteopontin (OPN), a secretory molecule, as one of most abundant molecules expressed in MDPCs. OPN provided a proliferative effect for MDPCs. MDPCs treated with OPN showed Akt activation, and inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway repressed the proliferative effect of OPN. Furthermore, OPN-pretreated MDPCs maintained their differentiation potential into endothelial and vascular smooth muscle cells. These findings indicate an important role of OPN as an autocrine/paracrine molecule in regulating the proliferative growth of muscle-derived angiogenic progenitor cells via the PI3K/Akt pathway.

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  • Stage-specific role of endogenous Smad2 activation in cardiomyogenesis of embryonic stem cells. 国際誌

    Ryoji Kitamura, Tomosaburo Takahashi, Norio Nakajima, Koji Isodono, Satoshi Asada, Hikaru Ueno, Tomomi Ueyama, Toshikazu Yoshikawa, Hiroaki Matsubara, Hidemasa Oh

    Circulation research   101 ( 1 )   78 - 87   2007年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The role of Smads and their specific ligands during cardiomyogenesis in ES cells was examined. Smad2 was activated bimodally in the early and late phases of cardiac differentiation, whereas Smad1 was activated after the middle phase. Nodal and Cripto were expressed in the early stage and then downregulated, whereas transforming growth factor-beta and activin were expressed only in the late phase. Suppression of early Smad2 activation by SB-431542 produced complete inhibition of endodermal and mesodermal induction but augmented neuroectodermal differentiation, followed by poor cardiomyogenesis, whereas inhibition during the late phase alone promoted cardiomyogenesis. Inhibitory effect of Smad2 on cardiomyogenesis in the late phase was mainly mediated by transforming growth factor-beta, and inhibition of transforming growth factor-beta-mediated Smad2 activation resulted in a greater replicative potential in differentiated cardiac myocytes and enhanced differentiation of nonmyocytes into cardiac myocytes. Thus, endogenous Smad2 activation is indispensable for endodermal and mesodermal induction in the early phase. In the late phase, endogenous transforming growth factor-beta negatively regulates cardiomyogenesis through Smad2 activation by modulating proliferation and differentiation of cardiac myocytes.

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  • Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration. 国際誌

    Kento Tateishi, Eishi Ashihara, Naofumi Takehara, Tetsuya Nomura, Shoken Honsho, Takuo Nakagami, Shigehiro Morikawa, Tomosaburo Takahashi, Tomomi Ueyama, Hiroaki Matsubara, Hidemasa Oh

    Journal of cell science   120 ( Pt 10 )   1791 - 800   2007年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent studies have shown that cardiac stem cells (CSCs) from the adult mammalian heart can give rise to functional cardiomyocytes; however, the definite surface markers to identify a definitive single entity of CSCs and the molecular mechanisms regulating their growth are so far unknown. Here, we demonstrate a single-cell deposition analysis to isolate individually selected CSCs from adult murine hearts and investigate the signals required for their proliferation and survival. Clonally proliferated CSCs express stem cell antigen-1 (Sca-1) with embryonic stem (ES) cell-like and mesenchymal cell-like characteristics and are associated with telomerase reverse transcriptase (TERT). Using a transgene that expresses a GFP reporter under the control of the TERT promoter, we demonstrated that TERT(GFP)-positive fractions from the heart were enriched for cells expressing Sca-1. Knockdown of Sca-1 transcripts in CSCs led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing CSC proliferation and survival after direct cell-grafting into ischemic myocardium require Sca-1 to upregulate the secreted paracrine effectors that augment neoangiogenesis and limit cardiac apoptosis. Thus, Sca-1 might be an essential component to promote CSC proliferation and survival to directly facilitate early engraftment, and might indirectly exert the effects on late cardiovascular differentiation after CSC transplantation.

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  • Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3beta signaling. 国際誌

    Kento Tateishi, Eishi Ashihara, Shoken Honsho, Naofumi Takehara, Tetsuya Nomura, Tomosaburo Takahashi, Tomomi Ueyama, Masaaki Yamagishi, Hitoshi Yaku, Hiroaki Matsubara, Hidemasa Oh

    Biochemical and biophysical research communications   352 ( 3 )   635 - 41   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent evidence suggested that human cardiac stem cells (hCSCs) may have the clinical application for cardiac repair; however, their characteristics and the regulatory mechanisms of their growth have not been fully investigated. Here, we show the novel property of hCSCs with respect to their origin and tissue distribution in human heart, and demonstrate the signaling pathway that regulates their growth and survival. Telomerase-active hCSCs were predominantly present in the right atrium and outflow tract of the heart (infant > adult) and had a mesenchymal cell-like phenotype. These hCSCs expressed the embryonic stem cell markers and differentiated into cardiomyocytes to support cardiac function when transplanted them into ischemic myocardium. Inhibition of Akt pathway impaired the hCSC proliferation and induced apoptosis, whereas inhibition of glycogen synthase kinase-3 (GSK-3) enhanced their growth and survival. We conclude that hCSCs exhibit mesenchymal features and that Akt/GSK-3beta may be crucial modulators for hCSC maintenance in human heart.

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  • Skeletal myosphere-derived progenitor cell transplantation promotes neovascularization in delta-sarcoglycan knockdown cardiomyopathy. 国際誌

    Tetsuya Nomura, Eishi Ashihara, Kento Tateishi, Satoshi Asada, Tomomi Ueyama, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    Biochemical and biophysical research communications   352 ( 3 )   668 - 74   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bone marrow cells have been shown to contribute to neovascularization in ischemic hearts, whereas their impaired maturation to restore the delta-sarcoglycan (delta-SG) expression responsible for focal myocardial degeneration limits their utility to treat the pathogenesis of cardiomyopathy. Here, we report the isolation of multipotent progenitor cells from adult skeletal muscle, based on their ability to generate floating-myospheres. Myosphere-derived progenitor cells (MDPCs) are distinguishable from myogenic C2C12 cells and differentiate into vascular smooth muscle cells and mesenchymal progeny. The mutation in the delta-SG has been shown to develop vascular spasm to affect sarcolemma structure causing cardiomyopathy. We originally generated delta-SD knockdown (KD) mice and transplanted MDPCs into the hearts. MDPCs enhanced neoangiogenesis and restored delta-SG expression in impaired vasculatures through trans-differentiation, leading to improvement of cardiac function associated with paracrine effectors secretion. We propose that MDPCs may be the promising progenitor cells in skeletal muscle to treat delta-sarcoglycan complex mutant cardiomyopathy.

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  • MicroRNA-1 facilitates skeletal myogenic differentiation without affecting osteoblastic and adipogenic differentiation. 国際誌

    Norio Nakajima, Tomosaburo Takahashi, Ryoji Kitamura, Koji Isodono, Satoshi Asada, Tomomi Ueyama, Hiroaki Matsubara, Hidemasa Oh

    Biochemical and biophysical research communications   350 ( 4 )   1006 - 12   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MicroRNAs (miRNAs) are small non-coding RNAs emerging as important post-transcriptional gene regulators. In this study, we examined the role of miR-1, an miRNA specifically expressed in cardiac and skeletal muscle tissue, on the myogenic, osteoblastic, and adipogenic differentiation of C2C12 cells. Upon induction of myogenic differentiation, miR-1 was robustly expressed. Retrovirus-mediated overexpression of miR-1 markedly enhanced expression of muscle creatine kinase, sarcomeric myosin, and alpha-actinin, while the effects on myogenin and MyoD expression were modest. Formation of myotubes was significantly augmented in miR-1-overexpressing cells, indicating miR-1 expression enhanced not only myogenic differentiation but also maturation into myotubes. In contrast, osteoblastic and adipogenic differentiation was not affected by forced expression of miR-1. Thus, the muscle-specific miRNA, miR-1, plays important roles in controlling myogenic differentiation and maturation in lineage-committed cells, rather than functioning in fate determination.

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  • [New era of cardiac stem cell therapy in heart failure].

    Hidemasa Oh

    Rinsho byori. The Japanese journal of clinical pathology   53 ( 1 )   61 - 9   2005年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Despite of plethora of reports on stem cell transplantation leading to neovascularization in infarct models, whether sustaining clinical benefit in post-myocardial infarction patients is manifested by myocyte repair remains unclear. Cardiac muscle regeneration in adult heart is thought to occur through the mobilization and differentiation of mesenchymal stem cells in bone marrow origin, however, recent studies have suggested that substantial cardiac stem cells may exist in the heart itself, repopulating the damaged cardiac muscle during injury or aging processes. The implications of cardiac stem cells-based myocyte plasticity have recently begun to define in human heart, neither arisen from bone marrow nor circulating precursors. Introduction of cardiac stem cells may improve myocardial function, but several hurdles exist and should be coaxed far beyond the clinical application of cardiac regenerative therapies. On-going investigations may lead to the discovery of mediators of cardiac stem cells migration, proliferation and differentiation that, in turn, might result in the mending of the broken heart after injury.

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  • Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. 国際誌

    Ioakim Spyridopoulos, Judith Haendeler, Carmen Urbich, Tim H Brummendorf, Hidemasa Oh, Michael D Schneider, Andreas M Zeiher, Stefanie Dimmeler

    Circulation   110 ( 19 )   3136 - 42   2004年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Cultivation of endothelial progenitor cells (EPCs) leads to premature replicative senescence, limiting ex vivo expansion for potential clinical cell therapy. Recent studies have linked senescence to the dysfunction of telomeres, the "ends" of chromosomes, via the so-called mitotic clock or culture-induced stress. The purpose of this study was to elucidate a possible role of telomere biology in the functional augmentation of EPCs by statins. METHODS AND RESULTS: Human EPCs were isolated from peripheral blood. Using flow cytometry after fluorescence in situ hybridization with a telomere-specific (C3TA2)3 peptide nucleic acid probe (Flow-FISH), we found mean telomere length in untreated EPCs from healthy subjects to range between 8.5+/-0.2 and 11.1+/-0.5 kb with no change over 6 days of culture, excluding telomere erosion as one cause for premature senescence. Although mean telomere length did not differ between statin-treated and untreated EPCs, atorvastatin (0.1 micromol/L) and mevastatin (1.0 micromol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein TRF2 (telomere repeat-binding factor), as shown by immunoblotting, whereas quantitative reverse transcription-polymerase chain reaction demonstrated no increase in TRF2 mRNA. Telomere dysfunction of EPCs was also paralleled by a 4-fold increase in the DNA damage checkpoint-kinase 2 (Chk2). Conversely, statin cotreatment or overexpression of TRF2 completely suppressed Chk2 induction. Finally, overexpression of a dominant negative mutant of the TRF2 protein abrogated statin-induced enhancement of migratory activity down to baseline values. CONCLUSIONS: Ex vivo culturing of EPCs leads to "uncapping" of telomeres, indicated by the loss of TRF2. Statin cotreatment of EPCs prevents impairment of their functional capacity by a TRF2-dependent, posttranscriptional mechanism. This is the first time a beneficial effect of statins on telomere biology has been described.

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  • Cardiac muscle plasticity in adult and embryo by heart-derived progenitor cells. 国際誌

    Hidemasa Oh, Xuan Chi, Steven B Bradfute, Yuji Mishina, Jennifer Pocius, Lloyd H Michael, Richard R Behringer, Robert J Schwartz, Mark L Entman, Michael D Schneider

    Annals of the New York Academy of Sciences   1015   182 - 9   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The evidence of cardiomyocyte proliferation in damaged heart implied cardiac regeneration might occur by resident or extra cardiac stem cells. However, the specification and origin of these cells remain unknown. Here, we report using fluorescence-activated cell sorting that cardiac progenitor cells resided in adult heart and colocalized with small capillary vessels, within the stem cell antigen (Sca-1) population expressing high telomerase activity. Notably, hematopoietic stem cells capable of efflux Hoechst 33342, termed side population cells, also were identified within the heart-derived cells. The cardiac progenitor cells (CD45(-)/CD34(-)) express neither cardiac muscle nor endothelial cell markers at an undifferentiated stage. The exposure of 5-azacytidine induced cardiac differentiation, which depends, in part, on Bmpr1a, a type IA receptor for bone morphogenetic protein (BMP). The capability of adult Sca1(+) cells to adopt a cardiac muscle in embryogenesis was substantiated by blastocyst injection, using progenitors from the adult hearts of transgenic mice that harbor a bacterial artificial chromosome expressing GFP via the Nkx-2.5 locus. Intravenously injected progenitors, shortly after ischemic/reperfusion, homed and functionally differentiated 3.5% of total left ventricle in the host myocardium. Differentiation included both fusion-independent and fusion-associated components, proved by the Cre/loxP donor/recipient system. Our studies suggest that endogenous cardiac progenitors reside in the adult heart, regenerate cardiomyocytes functionally, and integrate into the existing heart circuitry.

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  • Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. 国際誌

    Hidemasa Oh, Steven B Bradfute, Teresa D Gallardo, Teruya Nakamura, Vinciane Gaussin, Yuji Mishina, Jennifer Pocius, Lloyd H Michael, Richard R Behringer, Daniel J Garry, Mark L Entman, Michael D Schneider

    Proceedings of the National Academy of Sciences of the United States of America   100 ( 21 )   12313 - 8   2003年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor Nkx2.5 but differentiate in vitro in response to 5'-azacytidine, in part depending on Bmpr1a, a receptor for bone morphogenetic proteins. Given intravenously after ischemia/reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre/Lox donor/recipient pair (alphaMHC-Cre/R26R), differentiation was shown to occur roughly equally, with and without fusion to host cells.

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  • Telomere attrition and Chk2 activation in human heart failure. 国際誌

    Hidemasa Oh, Sam C Wang, Arun Prahash, Motoaki Sano, Christine S Moravec, George E Taffet, Lloyd H Michael, Keith A Youker, Mark L Entman, Michael D Schneider

    Proceedings of the National Academy of Sciences of the United States of America   100 ( 9 )   5378 - 83   2003年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The "postmitotic" phenotype in adult cardiac muscle exhibits similarities to replicative senescence more generally and constitutes a barrier to effective restorative growth in heart disease. Telomere dysfunction is implicated in senescence and apoptotic signaling but its potential role in heart disorders is unknown. Here, we report that cardiac apoptosis in human heart failure is associated specifically with defective expression of the telomere repeat- binding factor TRF2, telomere shortening, and activation of the DNA damage checkpoint kinase, Chk2. In cultured cardiomyocytes, interference with either TRF2 function or expression triggered telomere erosion and apoptosis, indicating that cell death can occur via this pathway even in postmitotic, noncycling cells; conversely, exogenous TRF2 conferred protection from oxidative stress. In vivo, mechanical stress was sufficient to down-regulate TRF2, shorten telomeres, and activate Chk2 in mouse myocardium, and transgenic expression of telomerase reverse transcriptase conferred protection from all three responses. Together, these data suggest that apoptosis in chronic heart failure is mediated in part by telomere dysfunction and suggest an essential role for TRF2 even in postmitotic cells.

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  • Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. 国際誌

    Motoaki Sano, Maha Abdellatif, Hidemasa Oh, Min Xie, Luigi Bagella, Antonio Giordano, Lloyd H Michael, Francesco J DeMayo, Michael D Schneider

    Nature medicine   8 ( 11 )   1310 - 7   2002年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.

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  • The emerging role of telomerase in cardiac muscle cell growth and survival. 国際誌

    Hidemasa Oh, Michael D Schneider

    Journal of molecular and cellular cardiology   34 ( 7 )   717 - 24   2002年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Most mammalian cells-excepting germ cells, tumor cells, and stem cells, that is-possess a finite replicative life span, manifested by the eventual cessation of cell proliferation. Clinically, this is germane not just to the overt derangements of cell growth in cancer, but also to organs such as the heart, in which the capacity for cell replacement and repair is insufficient to maintain organ function following cell death. Among the intrinsic mechanisms that control a conserved program of replicative senescence is the enzyme telomerase, which synthesizes the telomeric repeat for end-capping of each chromosome. The implications of telomerase for cardiac growth have recently begun to be defined. Other functions of telomerase, in maintaining genome integrity, also hold importance for cardiac muscle, as a novel means to suppress apoptosis and, thus, salvage myocardium following ischemic injury.

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▼全件表示

書籍等出版物

  • Stem cellを用いた治療

    平井健太, 王 英正( 担当: 共著)

    2021年7月 

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  • ヒト心筋幹細胞移植療法の前臨床的確立と細胞組織工学によるハイブリッド療法の開発に関する総合的研究

    王, 英正, 京都大学大学院医学研究科

    [王英正]  2008年5月 

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    総ページ数:1冊  

    CiNii Books

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MISC

  • 小児循環器疾患に対する再生医療 1 Stem Cellを用いた治療

    平井健太, 王英正

    小児科   62 ( 6 )   2021年

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  • 小児拡張型心筋症における心臓修復のための心臓球由来エキソソームマイクロRNA: 前臨床および安全性リードイン第1相臨床試験【JST・京大機械翻訳】|||

    平井健太, 大月審一, 王英正

    日本循環器学会学術集会(Web)   85th   2021年

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  • 小児心臓内幹細胞における無血清培地を用いた細胞増殖および性質評価に関わる基礎的検討

    逢坂大樹, 後藤拓弥, 平井健太, 笠原真悟, 王英正

    日本再生医療学会総会(Web)   18th   2019年

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  • エキソソームは拡張型心筋症のブタモデルにおける心臓前駆細胞の心筋再生を仲介する【JST・京大機械翻訳】|||

    王英正, 平井健太, 後藤拓弥, 逢坂大樹, 大月審一

    日本循環器学会学術集会(Web)   83rd   2019年

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  • Impact of cardiac progenitor cells on heart failure and survival in single ventricle congenital heart disease.

    Sano T, Ousaka D, Goto T, Ishigami S, Hirai K, Kasahara S, Ohtsuki S, Sano S, Oh H

    Circulation Research   122 ( 7 )   994 - 1005   2018年

  • Impact of cardiac progenitor cells on heart failure and survival in single ventricle congenital heart disease.

    Sano T, Ousaka D, Goto T, Ishigami S, Hirai K, Kasahara S, Ohtsuki S, Sano S, Oh H

    Circulation Research   122 ( 7 )   994 - 1005   2018年

  • 下大静脈絞扼を用いたプレコンディショニング戦略は大動物フォンタンモデル作成時の急激な循環変動を抑制する

    逢坂大樹, 後藤拓弥, 佐野俊和, 平井健太, 笠原真悟, 王英正

    日本小児循環器学会雑誌   34 ( Supplement 1 )   2018年

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  • 拡張型心筋症の新規ブタモデルにおける心臓前駆細胞送達【JST・京大機械翻訳】|||

    佐野俊和, 平井健太, 後藤拓弥, 逢坂大樹, 大月審一, 王英正

    日本循環器学会学術集会(Web)   82nd   2018年

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  • 単心室における心臓前駆細胞適用後の臨床転帰:駆出率保持心不全の影響【JST・京大機械翻訳】|||

    佐野俊和, 逢坂大樹, 平井健太, 後藤拓弥, 笠原真悟, 大月審一, 王英正

    日本循環器学会学術集会(Web)   82nd   2018年

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  • 大型動物の下大静脈絞扼モデルを用いた腹部臓器うっ血による臓器障害評価

    後藤拓弥, 逢坂大樹, 佐野俊和, 平井健太, 笠原真悟, 王英正

    日本小児循環器学会雑誌   34 ( Supplement 1 )   2018年

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  • 非移植群とretrospectiveに比較した機能的単心室症に対する心臓内幹細胞移植の有効性評価

    佐野俊和, 逢坂大樹, 後藤拓弥, 平井健太, 石神修大, 笠原真悟, 大月審一, 佐野俊二, 王英正

    日本再生医療学会総会(Web)   17th   2018年

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  • 新しいブタ拡張型心筋症モデルの開発と心臓内幹細胞治療

    平井健太, 大月審一, 佐野俊和, 後藤拓弥, 逢坂大樹, 王英正

    日本再生医療学会総会(Web)   17th   2018年

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  • Cell Therapy Trials in Congenital Heart Disease

    Hidemasa Oh

    CIRCULATION RESEARCH   120 ( 8 )   1353 - 1366   2017年4月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Dramatic evolution in medical and catheter interventions and complex surgeries to treat children with congenital heart disease (CHD) has led to a growing number of patients with a multitude of long-term complications associated with morbidity and mortality. Heart failure in patients with hypoplastic left heart syndrome predicated by functional single ventricle lesions is associated with an increase in CHD prevalence and remains a significant challenge. Pathophysiological mechanisms contributing to the progression of CHD, including single ventricle lesions and dilated cardiomyopathy, and adult heart disease may inevitably differ. Although therapeutic options for advanced cardiac failure are restricted to heart transplantation or mechanical circulatory support, there is a strong impetus to develop novel therapeutic strategies. As lower vertebrates, such as the newt and zebrafish, have a remarkable ability to replace lost cardiac tissue, this intrinsic self-repair machinery at the early postnatal stage in mice was confirmed by partial ventricular resection. Although the underlying mechanistic insights might differ among the species, mammalian heart regeneration occurs even in humans, with the highest degree occurring in early childhood and gradually declining with age in adulthood, suggesting the advantage of stem cell therapy to ameliorate ventricular dysfunction in patients with CHD. Although effective clinical translation by a variety of stem cells in adult heart disease remains inconclusive with respect to the improvement of cardiac function, case reports and clinical trials based on stem cell therapies in patients with CHD may be invaluable for the next stage of therapeutic development. Dissecting the differential mechanisms underlying progressive ventricular dysfunction in children and adults may lead us to identify a novel regenerative therapy. Future regenerative technologies to treat patients with CHD are exciting prospects for heart regeneration in general practice.

    DOI: 10.1161/CIRCRESAHA.117.309697

    Web of Science

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  • Intracoronary Cardiac Progenitor Cells in Single Ventricle Physiology The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) Randomized Phase 2 Trial

    Shuta Ishigami, Shinichi Ohtsuki, Takahiro Eitoku, Daiki Ousaka, Maiko Kondo, Yoshihiko Kurita, Kenta Hirai, Yosuke Fukushima, Kenji Baba, Takuya Goto, Naohiro Horio, Junko Kobayashi, Yosuke Kuroko, Yasuhiro Kotani, Sadahiko Arai, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION RESEARCH   120 ( 7 )   1162 - +   2017年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Rationale: Patients with single ventricle physiology are at high risk of mortality resulting from ventricular dysfunction. The preliminary results of the phase 1 trial showed that cardiosphere-derived cells (CDCs) may be effective against congenital heart failure.
    Objective: To determine whether intracoronary delivery of autologous CDCs improves cardiac function in patients with single ventricle physiology.
    Methods and Results: We conducted a phase 2 randomized controlled study to assign in a 1: 1 ratio 41 patients who had single ventricle physiology undergoing stage 2 or 3 palliation to receive intracoronary infusion of CDCs 4 to 9 weeks after surgery or staged reconstruction alone (study A). The primary outcome measure was to assess improvement in cardiac function at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC infusion on request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in the controls (+ 6.4% [SD, 5.5] versus + 1.3% [SD, 3.7]; P= 0.003). In study B, a late CDC infusion in 17 controls increased the ventricular function at 3 months compared with that at baseline (38.8% [SD, 7.7] versus 34.8% [SD, 7.4]; P&lt; 0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD, 6.6] versus 35.0% [SD, 8.2]; P&lt; 0.0001) and volumes (P&lt; 0.001), somatic growth (P&lt; 0.0001) with increased trophic factors production, such as insulin-like growth factor-1 and hepatocyte growth factor, and quality of life, along with a reduced heart failure status (P&lt; 0.0001) and cardiac fibrosis (P= 0.014) relative to baseline.
    Conclusions: Intracoronary infusion of CDCs after staged palliation favorably affected cardiac function by reverse remodeling in patients with single ventricle physiology. This impact may improve heart failure status, somatic growth, and quality of life in patients and reduce parenting stress for their families.

    DOI: 10.1161/CIRCRESAHA.116.310253

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  • Transcoronary cell infusion with the stop-flow technique in children with single-ventricle physiology.

    Eitoku T, Baba K, Kondou M, Kurita Y, Fukushima Y, Hirai K, Ohtsuki S, Ishigami S, Sano S, Oh H

    Pediatric Intervention   60 ( 3 )   240 - 246   2017年

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  • 体性幹細胞を用いた心臓再生医療の最前線

    石神修大, 大月審一, 笠原真悟, 佐野俊二, 王 英正

    臨床医薬   33 ( 4 )   125 - 132   2017年

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  • Cell Therapy Trials in Congenital Heart Disease

    H. Oh

    Circulation Research   120 ( 8 )   1353 - 1366   2017年

  • Transcoronary cell infusion with the stop-flow technique in children with single-ventricle physiology.

    Eitoku T, Baba K, Kondou M, Kurita Y, Fukushima Y, Hirai K, Ohtsuki S, Ishigami S, Sano S, Oh H

    Pediatric Intervention   60 ( 3 )   240 - 246   2017年

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  • 先天性心疾患に対する心筋再生医療

    石神修大, 大月審一, 笠原真悟, 佐野俊二, 王 英正

    Heart View   5 ( 5 )   547 - 551   2017年

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  • Cell Therapy Trials in Congenital Heart Disease

    Oh H

    Circulation Research   120 ( 8 )   1353 - 1366   2017年

  • メカノ医工学を駆使した再生医療・生殖医療への展開 招待

    高橋 賢, 王 英正, 入部 玄太郎, 松浦 宏治, 成瀬 恵治

    生体医工学   55 ( 4PM-Abstract )   340 - 340   2017年

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)   出版者・発行元:公益社団法人 日本生体医工学会  

    <p>近年メカノバイオロジーを基盤とした研究手法は、様々な疾患の成因解明と治療法開発というメカノメディスンへと昇華し始めている。本講演はメカノ再生医療とメカノ生殖医療のトランスレーショナルリサーチの展開による、臨床利用可能な革新的次世代メカノ医療技術について紹介する。やけどなど皮膚の損傷に対し再生医療の応用が期待されている。我々は独自に開発した細胞培養器を用い、表皮角化細胞と皮膚線維芽細胞の共培養を行って伸展刺激を付加したところ、表皮層の増高と基底膜形成の促進が認められた。また心不全患者に対しては心臓再生医療の応用が期待されている。心臓再生医療では、幹細胞に対する伸展刺激は細胞分化能や生着性を変化させて細胞治療の効果を改善すると考えられてきたが、幹細胞より直接遊離するエクソソームが様々なパラクライン因子やmicro RNAを分泌することで、in vivoでの細胞移植治療の効果を向上させていることが明らかとなった。生殖補助医療においては、体外受精卵の生育率の低さが大きな問題である。我々は受精卵にメカニカルストレスを付加する傾斜胚培養システムを用いて受精卵培養したところ、受精卵の胚盤胞到達率が静置培養区と比較して向上した。遺伝子発現網羅的解析の結果から、この現象は胚盤葉上層の遺伝子発現変化に起因することが示唆された。今後も各分野における機械刺激応答のメカニズム解明に注力するとともに、メカノ医療技術の臨床応用を進めていく。</p>

    DOI: 10.11239/jsmbe.55Annual.340

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  • HFpEF(heart failure with preserved ejection fraction)に対する心臓内幹細胞移植の有効性

    逢坂大樹, 後藤拓弥, 石神修大, 佐野俊和, 平井健太, 大月審一, 笠原真悟, 佐野俊二, 王英正

    日本循環器学会学術集会(Web)   81st   2017年

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  • 単一室循環は単心室心臓の子ブタモデルにおける心臓前駆細胞の静脈内送達後の細胞移植を増強する【JST・京大機械翻訳】|||

    王英正, 後藤拓弥, 逢坂大樹, 佐野俊和, 平井健太, 笠原真悟, 佐野俊二

    日本循環器学会学術集会(Web)   81st   2017年

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  • 自己心臓内幹細胞移植 そのテクニックについて

    栄徳隆裕, 大月審一, 馬場健児, 近藤麻衣子, 栗田佳彦, 重光祐輔, 平井健太, 石上修大, 笠原真悟, 王英正

    日本小児循環器学会雑誌   33 ( Supplement 1 )   2017年

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  • 機能的単心室症に対する細胞治療法における第1/2相臨床研究の2年追跡調査

    佐野俊和, 石神修大, 逢坂大樹, 平井健太, 後藤拓哉, 笠原真悟, 大月晋一, 佐野俊二, 王英正

    日本胸部外科学会定期学術集会(Web)   70th   2017年

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  • 新しいブタ拡張型心筋症モデルの作成と心臓内幹細胞治療

    平井健太, 大月審一, 佐野俊和, 後藤拓弥, 逢坂大樹, 王英正

    日本小児心筋疾患学会学術集会プログラム・抄録集   26th   2017年

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  • HFpEF(heart failure with preserved ejection fraction)における心臓内幹細胞移植の治療効果と機序解明

    逢坂大樹, 後藤拓弥, 石神修大, 佐野俊和, 平井健太, 大月審一, 笠原真悟, 佐野俊二, 王英正

    再生医療   16   2017年

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  • 単心室循環の血行動態に着目した心臓内幹細胞静脈投与療法

    後藤拓弥, 逢坂大樹, 平井健太, 佐野俊和, 王英正

    再生医療   16   2017年

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  • Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases

    Hidemasa Oh, Hiroshi Ito, Shunji Sano

    JOURNAL OF CARDIOLOGY   68 ( 5-6 )   361 - 367   2016年11月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:ELSEVIER SCIENCE BV  

    Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases. (C) 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jjcc.2016.04.010

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  • Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases

    Hidemasa Oh, Hiroshi Ito, Shunji Sano

    JOURNAL OF CARDIOLOGY   68 ( 5-6 )   361 - 367   2016年11月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:ELSEVIER SCIENCE BV  

    Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases. (C) 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jjcc.2016.04.010

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  • Cardiac Progenitor Cell Therapy in Right Heart Failure With Preserved Ejection Fraction

    Daiki Ousaka, Takuya Goto, Shuta Ishigami, Toshikazu Sano, Kenta Hirai, Shinichi Ohtsuki, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION   134   2016年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • 心臓内幹細胞による心不全疾患の治療

    佐野俊和, 大月審一, 佐野俊二, 王 英正

    BIO Clinica   31 ( 10 )   29 - 33   2016年

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  • 心臓内幹細胞を用いた心臓再生医療

    平井健太, 大月審一, 佐野俊二, 王 英正

    心臓   48 ( 12 )   1334 - 1339   2016年

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  • 心臓再生治療の現状と展望 心臓幹細胞を用いた心臓再生治療

    平井健太, 大月審一, 佐野俊二, 王英正

    心臓   48 ( 12 )   2016年

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  • 機能的単心室症の児童のための自己心臓内幹細胞の冠動脈内注入

    栄徳隆裕, 大月審一, 馬場健児, 近藤麻衣子, 栗田佳彦, 福嶋遥佑, 重光祐輔, 平井健太, 王英正, 佐野俊二, 笠原真悟

    日本小児循環器学会雑誌   32 ( Supplement 1 )   2016年

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  • 単心室循環の血行動態に着目した経静脈的細胞投与による心筋再生医療の新たな可能性

    後藤拓弥, 逢坂大樹, 石神修大, 平井健太, 高橋生, 笠原真悟, 佐野俊二, 王英正

    日本小児循環器学会雑誌   32 ( Supplement 1 )   2016年

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  • 冠動脈バルーン閉鎖下心筋幹細胞注入の実際

    栄徳隆裕, 大月審一, 馬場健児, 近藤麻衣子, 栗田佳彦, 福嶋遥佑, 重光祐輔, 平井健太, 王英正, 佐野俊二, 岩崎達雄

    日本Pediatric Interventional Cardiology学会学術集会プログラム抄録集   27th   2016年

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  • Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial

    John E. Mayer, Sano, Todd Rosengart

    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY   150 ( 5 )   1207 - 1208   2015年11月

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    記述言語:英語   出版者・発行元:MOSBY-ELSEVIER  

    DOI: 10.1016/j.jtcvs.2015.06.076.

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  • Cardiac Progenitor Cell Infusion in Patients With Univentricular Heart Diseases in Heart Failure With Preserved Ejection Fraction

    Daiki Ousaka, Takuya Goto, Shuta Ishigami, Shinichi Ohtsuki, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION   132   2015年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Transcoronary Infusion of Cardiac Progenitor Cells in Hypoplastic Left Heart Syndrome: 3-year Results of the TICAP Trial

    Shuta Ishigami, Suguru Tarui, Takuya Goto, Daiki Ousaka, Kenji Baba, Shingo Kasahara, Shinichi Ohtsuki, Shunji Sano, Hidemasa Oh

    CIRCULATION   132   2015年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome The TICAP Prospective Phase 1 Controlled Trial

    Shuta Ishigami, Shinichi Ohtsuki, Suguru Tarui, Daiki Ousaka, Takahiro Eitoku, Maiko Kondo, Michihiro Okuyama, Junko Kobayashi, Kenji Baba, Sadahiko Arai, Takuya Kawabata, Ko Yoshizumi, Atsushi Tateishi, Yosuke Kuroko, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION RESEARCH   116 ( 4 )   653 - 664   2015年2月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function.
    Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome.
    Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8 +/- 1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4 +/- 8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%+/- 4.6% to 52.1%+/- 2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%+/- 6.8% versus 40.4%+/- 7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007).
    Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes.

    DOI: 10.1161/CIRCRESAHA.116.304671

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  • Epigenetic modification in congenital heart diseases by using stem cell technologies

    Kobayashi J, Sano S, Oh H

    Stem Cell Epigenetics   1 ( 2 )   e550   2015年

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  • Cardiac stem cell therapies for congenital heart diseases

    Ishigami S, Sano S, Oh H

    Stem Cell and Translational Investigation   1 ( 2 )   e800   2015年

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  • 小児心不全に対する心臓内幹細胞自家移植療法

    日本小児血液・がん学会誌   52 ( 3 )   2015年

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  • 疾患特異的iPS細胞を用いた先天性心疾患の病態解明

    小児循環器学会雑誌   2015年

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  • Cardiac Magnetic Resonance Late Gadolinium Enhancement is Associated With Ventricular Elastance That May Predict Latent Ventricular Dysfunction After Fontan Procedure

    Michihiro Okuyama, Shuta Ishigami, Daiki Ousaka, Junko Kobayashi, Sadahiko Arai, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION   130   2014年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Intracoronary Delivery of Autologous Cardiac Progenitor Cells in Children With Hypoplastic Left Heart Syndrome: The Ticap Trial With 18-Month Follow Up

    Shuta Ishigami, Suguru Tarui, Michihiro Okuyama, Daiki Ousaka, Shinichi Ohtsuki, Takahiro Eitoku, Junko Kobayashi, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION   130   2014年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Disease-Specific Induced Pluripotent Stem Cells Identify the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 During Cardiac Development of Hypoplastic Left Heart Syndrome

    Junko Kobayashi, Masashi Yoshida, Suguru Tarui, Shuta Ishigami, Michihiro Okuyama, Yusuke Nagai, Shingo Kasahara, Keiji Naruse, Hiroshi Ito, Shunji Sano, Hidemasa Oh

    CIRCULATION   130   2014年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome

    Junko Kobayashi, Masashi Yoshida, Suguru Tarui, Masataka Hirata, Yusuke Nagai, Shingo Kasahara, Keiji Naruse, Hiroshi Ito, Shunji Sano, Hidemasa Oh

    PLOS ONE   9 ( 7 )   e102796-e102796   2014年7月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS-and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS-and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS.

    DOI: 10.1371/journal.pone.0102796

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  • MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors.

    Ogata T, Naito D, Nakanishi N, Hayashi YK, Taniguchi T, Miyagawa K, Hamaoka T, Maruyama N, Matoba S, Ikeda K, Yamada H, Oh H, Ueyama T

    Proc Natl Acad Sci U S A.   111 ( 10 )   3811 - 3816   2014年3月

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  • Stem cell therapies in patients with single ventricle physiology.

    Methodist Debakey Cardiovascular Journal.   10 ( 2 )   77 - 81   2014年

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  • 小児心不全の再生医療からのアプローチ

    石神修大, 佐野俊二, 王 英正

    移植   50 ( 6 )   54 - 63   2014年

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  • 先天性心疾患外科手術における再生医療

    循環器内科   75 ( 1 )   87 - 93   2014年

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  • YT-11-5(YRA) 疾患特異的iPS細胞を用いた左心低形成症候群における心臓発生異常の解明(YT Young Researcher Award & Traveler's Grant,第113回日本外科学会定期学術集会)

    小林 純子, 樽井 俊, 平田 昌敬, 川畑 拓也, 黒子 洋介, 立石 篤史, 吉積 功, 新井 禎彦, 笠原 真悟, 佐野 俊二, 王 英正

    日本外科学会雑誌   114 ( 2 )   415 - 415   2013年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • 心筋幹細胞を用いた先天性心疾患に対する心筋再生医療

    樽井俊, 佐野俊二, 王 英正

    月刊循環器   3 ( 9 )   69 - 76   2013年

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  • Patient-specific Induced Pluripotent Stem Cells For Modeling Hypoplastic Left Heart Syndrome

    Junko Kobayashi, Masashi Yoshida, Suguru Tarui, Masataka Hirata, Ken Takahashi, Shingo Kasahara, Keiji Naruse, Hiroshi Ito, Shunji Sano, Hidemasa Oh

    CIRCULATION   126 ( 21 )   2012年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Factors-based Human Cardiomyocytes Differentiation Exhibits Defective Maturation and Excitation Through Aberrant Calcium Handling Proteins

    Suguru Tarui, Junko Kobayashi, Masataka Hirata, Ken Takahashi, Gentaro Iribe, Keiji Naruse, Shingo Kasahara, Shunji Sano, Hidemasa Oh

    CIRCULATION   126 ( 21 )   2012年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Cardiac Progenitor Cell Infusion in Patients with Hypoplastic Left Heart Syndrome: a Prospective Phase 1 Clinical Trial

    Hidemasa Oh, Suguru Tarui, Shinichi Otsuki, Shunji Sano

    JOURNAL OF CARDIAC FAILURE   18 ( 10 )   S145 - S145   2012年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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  • 先天性心疾患に対する心筋再生医療

    小林純子, 佐野俊二, 王 英正

    循環器内科   71 ( 4 )   360 - 368   2012年

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  • 小児心不全への細胞治療の現状と展望

    王 英正

    呼吸と循環   60   S1-S4   2012年

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  • 先天性心疾患に対する心筋再生医療

    小林純子, 佐野俊二, 王 英正

    循環器内科   71   360 - 368   2012年

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  • テロメア生物学から心筋再生医療の実用化へ

    王 英正

    岡山医学会雑誌   124 ( 1 )   27 - 34   2012年

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    記述言語:日本語   出版者・発行元:岡山医学会  

    DOI: 10.4044/joma.124.27

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    その他リンク: http://ousar.lib.okayama-u.ac.jp/48132

  • Molecular Genetic and Functional Characterization Implicate Muscle-Restricted Coiled-Coil Gene (MURC) as a Causal Gene for Familial Dilated Cardiomyopathy

    Gabriela Rodriguez, Tomomi Ueyama, Takehiro Ogata, Grazyna Czernuszewicz, Yanli Tan, Gerald W. Dorn, Roberta Bogaev, Katsuya Amano, Hidemasa Oh, Hiroaki Matsubara, James T. Willerson, Ali J. Marian

    CIRCULATION-CARDIOVASCULAR GENETICS   4 ( 4 )   349 - U47   2011年8月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background-Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies.
    Methods and Results-We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p. S307T segregated with inheritance of DCM in small families (chi(2) = 8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC.
    Conclusions-MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain. (Circ Cardiovasc Genet. 2011;4:349-358.)

    DOI: 10.1161/CIRCGENETICS.111.959866

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  • Molecular Genetic and Functional Characterization Implicate Muscle-Restricted Coiled-Coil Gene (MURC) as a Causal Gene for Familial Dilated Cardiomyopathy

    Gabriela Rodriguez, Tomomi Ueyama, Takehiro Ogata, Grazyna Czernuszewicz, Yanli Tan, Gerald W. Dorn, Roberta Bogaev, Katsuya Amano, Hidemasa Oh, Hiroaki Matsubara, James T. Willerson, Ali J. Marian

    CIRCULATION-CARDIOVASCULAR GENETICS   4 ( 4 )   349 - U47   2011年8月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background-Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies.
    Methods and Results-We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p. S307T segregated with inheritance of DCM in small families (chi(2) = 8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC.
    Conclusions-MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain. (Circ Cardiovasc Genet. 2011;4:349-358.)

    DOI: 10.1161/CIRCGENETICS.111.959866

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  • 新生児Ebstein奇形のManagement

    藤井泰宏, 新井禎彦, 石神修太, 樽井俊, 櫻井茂, 鵜垣伸也, 川畑拓也, 立石篤史, 藤田康文, 高垣昌巳, 平田昌敬, 笠原真悟, 三井秀也, 王英正, 佐野俊二

    日本心臓血管外科学会雑誌   40 ( Supplement )   199 - 199   2011年1月

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    記述言語:日本語   出版者・発行元:(NPO)日本心臓血管外科学会  

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  • 小児心不全への細胞治療

    樽井 俊, 佐野俊二, 王 英正

    Medical Science Digest   37   439 - 442   2011年

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  • 小児心不全に対する心筋再生療法.

    樽井 俊, 佐野俊二, 王 英正

    Medical Science Digest   37 ( 11 )   439 - 442   2011年

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  • PARM-1 Is an Endoplasmic Reticulum Molecule Involved in Endoplasmic Reticulum Stress-Induced Apoptosis in Rat Cardiac Myocytes

    Koji Isodono, Tomosaburo Takahashi, Hiroko Imoto, Naohiko Nakanishi, Takehiro Ogata, Satoshi Asada, Atsuo Adachi, Tomomi Ueyama, Hidemasa Oh, Hiroaki Matsubara

    PLOS ONE   5 ( 3 )   e9746-e9746   2010年3月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    To identify novel transmembrane and secretory molecules expressed in cardiac myocytes, signal sequence trap screening was performed in rat neonatal cardiac myocytes. One of the molecules identified was a transmembrane protein, prostatic androgen repressed message-1 (PARM-1). While PARM-1 has been identified as a gene induced in prostate in response to castration, its function is largely unknown. Our expression analysis revealed that PARM-1 was specifically expressed in hearts and skeletal muscles, and in the heart, cardiac myocytes, but not non-myocytes expressed PARM-1. Immunofluorescent staining showed that PARM-1 was predominantly localized in endoplasmic reticulum (ER). In Dahl salt-sensitive rats, high-salt diet resulted in hypertension, cardiac hypertrophy and subsequent heart failure, and significantly stimulated PARM-1 expression in the hearts, with a concomitant increase in ER stress markers such as GRP78 and CHOP. In cultured cardiac myocytes, PARM-1 expression was stimulated by proinflammatory cytokines, but not by hypertrophic stimuli. A marked increase in PARM-1 expression was observed in response to ER stress inducers such as thapsigargin and tunicamycin, which also induced apoptotic cell death. Silencing PARM-1 expression by siRNAs enhanced apoptotic response in cardiac myocytes to ER stresses. PARM-1 silencing also repressed expression of PERK and ATF6, and augmented expression of CHOP without affecting IRE-1 expression and JNK and Caspase-12 activation. Thus, PARM-1 expression is induced by ER stress, which plays a protective role in cardiac myocytes through regulating PERK, ATF6 and CHOP expression. These results suggested that PARM-1 is a novel ER transmembrane molecule involved in cardiac remodeling in hypertensive heart disease.

    DOI: 10.1371/journal.pone.0009746

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  • Stem Cell Engineering for Cardiac Tissue Regeneration

    Masashi Yoshida, Hidemasa Oh

    CARDIOLOGY   115 ( 3 )   191 - 193   2010年

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    記述言語:英語   出版者・発行元:KARGER  

    DOI: 10.1159/000281839

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  • Stem Cell Engineering for Cardiac Tissue Regeneration

    Masashi Yoshida, Hidemasa Oh

    CARDIOLOGY   115 ( 3 )   191 - 193   2010年

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    記述言語:英語   出版者・発行元:KARGER  

    DOI: 10.1159/000281839

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  • Deficiency of Nectin-2 Leads to Cardiac Fibrosis and Dysfunction Under Chronic Pressure Overload

    Seimi Satomi-Kobayashi, Tomomi Ueyama, Steffen Mueller, Ryuji Toh, Tomoya Masano, Tsuyoshi Sakoda, Yoshiyuki Rikitake, Jun Miyoshi, Hiroaki Matsubara, Hidemasa Oh, Seinosuke Kawashima, Ken-ichi Hirata, Yoshimi Takai

    HYPERTENSION   54 ( 4 )   825 - U268   2009年10月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca(2+)-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload induced cardiac dysfunction. (Hypertension. 2009; 54: 825-831.)

    DOI: 10.1161/HYPERTENSIONAHA.109.130443

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  • 5 Cardiac Regenerative Hybrid-therapy Integrated via Human Autologous Cardiac Stem Cell and Biodegradable bFGF-incorporating Gelatin Hydrogel(Therapeutic Strategy for Severe Heart Failure-From LVAD to Heart Transplantation-,Symposium 11 (SY-11) (H),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)

    Takehara Naofumi, Tsutsumi Yoshiaki, Amano Katsuya, Takahashi Tomosaburo, Yaku Hitoshi, Tabata Yasuhiko, Oh Hidemasa, Hasebe Naoyuki, Matsubara Hiroaki

    Circulation journal : official journal of the Japanese Circulation Society   73   43 - 43   2009年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Cardiosphereを用いた心筋再生医療

    中西直彦, 竹原有史, 中岡幹彦, 赤壁佳樹, 王 英正, 松原弘明

    総合臨床   2009年

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  • ヒト心臓由来幹細胞を用いた心不全への再生医療

    小出正洋, 星野 温, 山口真一郎, 岸田 聡, 竹原有史, 王 英正, 松原弘明

    再生誘導治療   2009年

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  • 心筋幹細胞

    王 英正

    循環器科 特集   2009年

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  • 重症心不全に対する細胞治療法

    竹原有史, 塘 義明, 天野克也, 王 英正, 長谷部直幸, 松原弘明

    循環器科 特集   2009年

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  • Cardiosphereを用いた心筋再生医療

    中岡幹彦, 竹原有史, 中西直彦, 赤壁佳樹, 王 英正, 松原弘明

    再生医療   2009年

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  • 自己心臓幹細胞を用いた心不全への細胞治療

    岸田 聡, 竹原有史, 王 英正, 松原弘明

    重症心不全の予防と治療   2009年

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  • 新しい心臓再生法

    王 英正

    Medical View Point   2009年

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  • Cardiosphereによる心筋再生

    竹原有史, 服部玲治, 松原弘明, 王 英正

    Annual Review 循環器   2009年

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  • Cardiosphereによる心筋再生医療

    山口真一郎, 竹原有史, 天野克也, 高橋知三郎, 王 英正, 松原弘明

    分子心血管病 特集   2009年

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  • 新規心筋細胞特異的膜蛋白PARM-1は,心筋細胞においてERストレス誘導性でありアポトーシスに対して抑制的に働いている

    五十殿弘二, 五十殿弘二, 高橋知三郎, 高橋知三郎, 井本裕子, 井本裕子, 小形岳寛, 浅田聡, 浅田聡, 足立敦郎, 足立敦郎, 上山知巳, 上山知巳, 王英正, 松原弘明, 松原弘明

    日本高血圧学会総会プログラム・抄録集   32nd   2009年

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  • Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis

    Satoshi Asada, Tomosaburo Takahashi, Koji Isodono, Atsuo Adachi, Hiroko Imoto, Takehiro Ogata, Tomomi Ueyama, Hiroaki Matsubara, Hidemasa Oh

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   295 ( 6 )   H2512 - H2521   2008年12月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis. Am J Physiol Heart Circ Physiol 295: H2512-H2521, 2008. First published October 31, 2008; doi:10.1152/ajpheart.00233.2008.-Although the modulated expression of Dicer is documented upon neoplastic transformation, little is known of the regulation of Dicer expression by environmental stimuli and its roles in the regulation of cellular functions in primary cells. In this study, we found that Dicer expression was downregulated upon serum withdrawal in human umbilical vein endothelial cells (HUVECs). Serum withdrawal induced a time-dependent repression of Dicer expression, which was specifically rescued by vascular endothelial cell growth factor or sphingosine-1-phosphate. When Dicer expression was silenced by short-hairpin RNA against Dicer, the cells were more prone to apoptosis under serum withdrawal, whereas the rate of apoptosis was comparable with control cells in the serum-containing condition. Real-time PCR-based gene expression profiling identified several genes, the expression of which was modulated by Dicer silencing, including adhesion and matrix-related molecules, caspase-3, and nitric oxide synthase 3 (NOS3). Dicer silencing markedly impaired migratory functions without affecting cell adhesion and repressed phosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 in adherent HUVECs. Dicer knockdown upregulated caspase-3 and downregulated NOS3 expression, and serum withdrawal indeed increased caspase-3 and decreased NOS3 expression. Furthermore, the overexpression of Dicer in HUVECs resulted in a marked reduction in apoptosis upon serum withdrawal and a decreased caspase-3 and increased NOS3 expression. The inhibition of NOS activity by N(omega)-nitro-L-arginine methyl ester abrogated the effect of Dicer overexpression to rescue the cells from serum withdrawal-induced apoptosis. These results indicated that serum withdrawal decreases Dicer expression, leading to an increased susceptibility to apoptosis through the regulation of caspase-3 and NOS3 expression.

    DOI: 10.1152/ajpheart.00233.2008

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  • Stemming heart failure with cardiac- or reprogrammed-stem cells

    Kento Tateishi, Naofumi Takehara, Hiroaki Matsubara, Hidemasa Oh

    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE   12 ( 6A )   2217 - 2232   2008年12月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:WILEY-BLACKWELL  

    Despite extensive efforts to control myocyte growth by genetic targeting of the cell cycle machinery and small molecules for cardiac repair, adult myocytes themselves appeared to divide a limited number of times in response to a variety of cardiac muscle stresses. Rare tissue-resident stem cells are thought to exist in many adult organs that are capable of self-renewal and differentiation and possess a range of actions that are potentially therapeutic. Recent studies suggest that a population of cardiac stem cells (CSCs) is maintained after cardiac development in the adult heart in mammals including human beings; however, homeostatic cardiomyocyte replacement might be stem cell-dependent, and functional myocardial regeneration after cardiac muscle damage is not yet considered as sufficient to fully maintain or reconstitute the cardiovascular system and function. Although it is clear that adult CSCs have limitations in their capabilities to proliferate extensively and differentiate in response to injury in vivo for replenishing mature car-diomyocytes and potentially function as resident stem cells. Transplantation of CSCs expanded ex vivo seems to require an integrated strategy of cell growth-enhancing factor(s) and tissue engineering technologies to support the donor cell survival and subsequent proliferation and differentiation in the host microenvironment. There has been substantial interest regarding the evidence that mammalian fibroblasts can be genetically reprogrammed to induced pluripotent stem (iPS) cells, which closely resemble embryonic stem (ES) cell properties capable of differentiating into functional cardiomyocytes, and these cells may provide an alternative cell source for generating patient-specific CSCs for therapeutic applications.

    DOI: 10.1111/j.1582-4934.2008.00487.x

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  • Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction

    Naofumi Takehara, Yoshiaki Tsutsumi, Kento Tateishi, Takehiro Ogata, Hideo Tanaka, Tomomi Ueyama, Tomosaburo Takahashi, Tetsuro Takamatsu, Masanori Fukushima, Masashi Komeda, Masaaki Yamagishi, Hitoshi Yaku, Yasuhiko Tabata, Hiroaki Matsubara, Hidemasa Oh

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   52 ( 23 )   1858 - 1865   2008年12月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    Objectives This study was designed to determine whether controlled release of basic fibroblast growth factor ( bFGF) might improve human cardiosphere-derived cell (hCDC) therapy in a pig model of chronic myocardial infarction.
    Background Current cell therapies for cardiac repair are limited by loss of the transplanted cells and poor differentiation.
    Methods We conducted 2 randomized, placebo-controlled studies in immunosuppressed pigs with anterior myocardial infarctions. Four weeks after coronary reperfusion, 14 pigs were randomly assigned to receive an intramyocardial injection of placebo medium with or without bFGF-incorporating hydrogel implantation. As a second study, 26 pigs were randomized to receive controlled release of bFGF combined with or without hCDCs or bone marrow-derived mesenchymal stem cell transplantation 4 weeks after reperfusion.
    Results Controlled release of bFGF in ischemic myocardium significantly augmented the formation of microvascular networks to enhance myocardial perfusion and contractile function. When combined with cell transplantation, the additive effects of bFGF were confined to hCDC-injected animals, but were not observed in animals receiving human bone marrow-derived mesenchymal stem cell transplantation. This was shown by increased donor-cell engraftment and enhanced cardiomyocyte differentiation in the transplanted hearts, resulting in synergistically improved ventricular function and regional wall motion and reduced infarct size.
    Conclusions Controlled delivery of bFGF modulates the post-ischemic microenvironment to enhance hCDC engraftment and differentiation. This novel strategy demonstrates significant functional improvements after myocardial infarction and may potentially represent a therapeutic approach to be studied in a clinical trial in human heart failure. (J Am Coll Cardiol 2008; 52: 1858-65) (c) 2008 by the American College of Cardiology Foundation

    DOI: 10.1016/j.jacc.2008.06.052

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  • Crossveinless-2 controls bone morphogenetic protein signaling during early cardiomyocyte differentiation in P19 cells

    Koichiro Harada, Akiko Ogai, Tomosaburo Takahashi, Masafumi Kitakaze, Hiroaki Matsubara, Hidemasa Oh

    JOURNAL OF BIOLOGICAL CHEMISTRY   283 ( 39 )   26705 - 26713   2008年9月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Increasing evidence indicates that bone morphogenetic proteins (BMPs) are crucial for cardiac induction, specification, and development. Although signaling of BMPs is tightly regulated through soluble BMP-binding proteins, how they regulate BMP signaling during cardiac differentiation remains unknown. To identify molecules responsible for BMP signaling during early cardiomyocyte differentiation of P19 cells, cDNA subtraction was performed. We found a bimodal expression of the BMP-binding protein Crossveinless-2 (Cv2) during cardiomyocyte differentiation; Cv2 is temporally expressed earlier than cardiac transcription factors such as Nkx2.5 and Tbx5 and acts as a suppressor for BMP signaling in P19 cells. We established a P19 clonal cell line harboring a cardiac alpha-myosin heavy chain promoter-driven enhanced green fluorescent protein gene to monitor cardiac differentiation by flow cytometry. Treatment with BMP2 during the first 2 days of differentiation suppressed cardiomyocyte differentiation through activation of downstream targets Smad1/5/8 protein and Id1 gene, whereas treatment with Cv2 conversely inhibited Smad1/5/8 activation and Id1 expression, leading to increased generation of cardiac cells. RNA interference-mediated knockdown (KD) of endogenous Cv2 showed increased Smad1/5/8 activation and impaired cardiomyocyte differentiation. Expression of cardiac mesoderm markers was reduced, whereas expression of Id1 and endoderm markers such as Sox7, Hnf4, and E-cadherin was induced in Cv2-kinase dead cells. These phenotypes were rescued by the addition of Cv2 protein to the culture media during the first 2 days of differentiation or co-culture with parental cells. These data suggest that Cv2 may specify cardiac mesodermal lineage through inhibition of BMP signaling at early stage of cardiogenesis.

    DOI: 10.1074/jbc.M801485200

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  • MURC, a muscle-restricted coiled-coil protein, is involved in the regulation of skeletal myogenesis

    Masashi Tagawa, Tomomi Ueyama, Takehiro Ogata, Naofumi Takehara, Norio Nakajima, Koji Isodono, Satoshi Asada, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY   295 ( 2 )   C490 - C498   2008年8月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Skeletal myogenesis is a multistep process by which multinucleated mature muscle fibers are formed from undifferentiated, mononucleated myoblasts. However, the molecular mechanisms of skeletal myogenesis have not been fully elucidated. Here, we identified muscle-restricted coiled-coil (MURC) protein as a positive regulator of myogenesis. In skeletal muscle, MURC was localized to the cytoplasm with accumulation in the Z-disc of the sarcomere. In C2C12 myoblasts, MURC expression occurred coincidentally with myogenin expression and preceded sarcomeric myosin expression during differentiation into myotubes. RNA interference (RNAi)-mediated knockdown of MURC impaired differentiation in C2C12 myoblasts, which was accompanied by impaired myogenin expression and ERK activation. Overexpression of MURC in C2C12 myoblasts resulted in the promotion of differentiation with enhanced myogenin expression and ERK activation during differentiation. During injury-induced muscle regeneration, MURC expression increased, and a higher abundance of MURC was observed in immature myofibers compared with mature myofibers. In addition, ERK was activated in regenerating tissue, and ERK activation was detected in MURC-expressing immature myofibers. These findings suggest that MURC is involved in the skeletal myogenesis that results from modulation of myogenin expression and ERK activation. MURC may play pivotal roles in the molecular mechanisms of skeletal myogenic differentiation.

    DOI: 10.1152/ajpcell.00188.2008

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  • PARM-1, a Novel Transmembrane Molecule Involved in Endoplasmic Reticulum Stress-Induced Apoptosis in Cardiac Myocytes

    Tomosaburo Takahashi, Koji Isodono, Takehiro Ogata, Satoshi Asada, Hiroko Imoto, Atsuo Adachi, Tomomi Ueyama, Hidemasa Oh, Hiroaki Matsubara

    CIRCULATION RESEARCH   103 ( 5 )   E63 - E63   2008年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • MURC, A Muscle-Restricted Coiled-Coil Protein, Induces Cardiomyocyte Hypertrophy Through the Extracellular Signal-Regulated Kinase Pathway

    Takehiro Ogata, Tomomi Ueyama, Koji Isodono, Hiroko Imoto, Masashi Tagawa, Norifumi Takehara, Satoshi Asada, Atsuo Adachi, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    CIRCULATION RESEARCH   103 ( 5 )   E57 - E57   2008年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance

    Takehiro Ogata, Tomomi Ueyama, Koji Isodono, Masashi Tagawa, Naofumi Takehara, Tsuneaki Kawashima, Koichiro Harada, Tomosaburo Takahashi, Tetsuo Shioi, Hiroaki Matsubara, Hidemasa Oh

    MOLECULAR AND CELLULAR BIOLOGY   28 ( 10 )   3424 - 3436   2008年5月

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    記述言語:英語   出版者・発行元:AMER SOC MICROBIOLOGY  

    We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.

    DOI: 10.1128/MCB.02186-07

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  • 心筋幹細胞移植治療における再生心筋の 2D Speckle Tracking echocardiography を用いた局所心筋機能評価

    竹原 有史, 塘 義明, 田畑 泰彦, 松原 弘明, 王 英正

    Japanese journal of medical ultrasonics = 超音波医学   35   S352   2008年4月

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  • Regeneration therapy for cardiac repair by autologous human heart-derived stem cells from biopsy samples

    Hiroaki Matsubara, Kento Tateishi, Hidemasa Oh

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   44 ( 2 )   435 - 435   2008年2月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.yjmcc.2007.07.005

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  • Secreted phosphoprotein 1 enhances proliferative self-renewal through PI3K/Akt signaling in skeletal myosphere-derived progenitor cells

    Takehiro Ogata, Tomomi Ueyama, Tetsuya Nomura, Satoshi Asada, Masashi Tagawa, Tomoyuki Makamura, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   44 ( 2 )   448 - 449   2008年2月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.yjmcc.2007.07.042

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  • Skeletal muscle-derived progenitors capable of differentiating into cardiomyocytes proliferate through myostatin-independent TGF-beta family signaling

    Tetsuya Nomura, Tomomi Ueyama, Eishi Ashihara, Kento Tateishi, Satoshi Asada, Norio Nakajima, Koji Isodono, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   365 ( 4 )   863 - 869   2008年1月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The existence of skeletal muscle-derived stem cells (MDSCs) has been suggested in mammals; however, the signaling pathways controlling MDSC proliferation remain largely unknown. Here we report the isolation of myosphere-derived progenitor cells (MDPCs) that can give rise to beating cardiomyocytes from adult skeletal muscle. We identified that follistatin, an antagonist of TGF-beta family members, was predominantly expressed in MDPCs, whereas myostatin was mainly expressed in myogenic cells and mature skeletal muscle. Although follistatin enhanced the replicative growth of MDPCs through Smad2/3 inactivation and cell cycle progression, disruption of myostatin did not increase the MDPC proliferation. By contrast, inhibition of activin A (ActA) or growth differentiation factor 11 (GDF11) signaling dramatically increased MDPC proliferation via down-regulation of p21 and increases in the levels of cdk2/4 and cyclin D1. Thus, follistatin may be an effective progenitor-enhancing agent neutralizing ActA and GDF11 signaling to regulate the growth of MDPCs in skeletal muscle. (C) 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2007.11.087

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  • 心臓組織内幹細胞を用いた心不全への心筋再生医療の現状

    王 英正

    心電図   2008年

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  • 心臓内幹細胞の特性と自己複製制御機構

    王 英正, 立石健人, 松原弘明

    実験医学 増刊号   2008年

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  • 心不全への再生医療

    足立淳郎, 井本裕子, 山口真一郎, 竹原有史, 王 英正, 松原弘明

    心不全診療マニュアル   2008年

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  • Therapeutic potential of stem/progenitor cells in human skeletal muscle for cardiovascular regeneration

    Tetsuya Nomura, Eishi Ashihara, Kento Tateishi, Tomomi Ueyama, Tomosaburo Takahashi, Masaaki Yamagishi, Toshikazu Kubo, Hitoshi Yaku, Hiroaki Matsubara, Hidemasa Oh

    Current Stem Cell Research and Therapy   2 ( 4 )   293 - 300   2007年12月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    Although myoblast transplantation in patients with ischemic heart failure results in a significant improvement of cardiac function, subsequent studies have consistently shown the myotubes formation in the absence of electromechanical coupling with the neighboring host myocardium, accompanied with the short-term release of paracrine effectors from implanted cells. One major pitfall of using myoblasts is that transplanted cells do not differentiate into cardiomyocytes, which may cause the inherent proarrhythmogenic events. Therefore, whether a discrete subpopulation in heterogeneous muscle-cell cultures is responsible for substantial cardiovascular regeneration has yet to be investigated. We describe here the isolation of progenitor cells from human skeletal muscle. These cells proliferated as non-adherent myospheres in suspension and displayed early embryonic factors and mesenchymal cell-like characteristics. Flow cytometric analyses demonstrated that CD56/N-CAM/Leu-19, a neural cell adhesion molecule abundantly present in myoblasts, was absent in myospheres but was expressed in an adherent cell population containing myogenic precursors. Myosphere-derived progenitor cells (MDPCs) differentiated in culture to produce cardiac, smooth muscle, and endothelial cells. Transplantation of MDPCs into ischemic hearts in NOD/scid mice promoted angiogenesis with substantial cardiovascular regeneration. Our results provide a foundation to further study the cell and biological function of human MDPCs which may have potential therapeutic implications. © 2007 Bentham Science Publishers Ltd.

    DOI: 10.2174/157488807782793808

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  • Stage-specific role of endogenous Smad2 activation in cardiomyogenesis of embryonic stem cells

    Ryoji Kitamura, Tomosaburo Takahashi, Norio Nakajima, Koji Isodono, Satoshi Asada, Hikaru Ueno, Tomomi Ueyama, Toshikazu Yoshikawa, Hiroaki Matsubara, Hidemasa Oh

    CIRCULATION RESEARCH   101 ( 1 )   78 - 87   2007年7月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    The role of Smads and their specific ligands during cardiomyogenesis in ES cells was examined. Smad2 was activated bimodally in the early and late phases of cardiac differentiation, whereas Smad1 was activated after the middle phase. Nodal and Cripto were expressed in the early stage and then downregulated, whereas transforming growth factor-beta and activin were expressed only in the late phase. Suppression of early Smad2 activation by SB- 431542 produced complete inhibition of endodermal and mesodermal induction but augmented neuroectodermal differentiation, followed by poor cardiomyogenesis, whereas inhibition during the late phase alone promoted cardiomyogenesis. Inhibitory effect of Smad2 on cardiomyogenesis in the late phase was mainly mediated by transforming growth factor-beta, and inhibition of transforming growth factor-beta- mediated Smad2 activation resulted in a greater replicative potential in differentiated cardiac myocytes and enhanced differentiation of nonmyocytes into cardiac myocytes. Thus, endogenous Smad2 activation is indispensable for endodermal and mesodermal induction in the early phase. In the late phase, endogenous transforming growth factor-beta negatively regulates cardiomyogenesis through Smad2 activation by modulating proliferation and differentiation of cardiac myocytes.

    DOI: 10.1161/CIRCRESAHA.106.147264

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  • Osteopontin is a myosphere-derived secretory molecule that promotes angiogenic progenitor cell proliferation through the phosphoinositide 3-kinase/Akt pathway

    Takehiro Ogata, Tomomi Ueyama, Tetsuya Nomura, Satoshi Asada, Masashi Tagawa, Tomoyuki Nakamura, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   359 ( 2 )   341 - 347   2007年7月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    We have reported that skeletal myosphere-derived progenitor cells (MDPCs) can differentiate into vascular cells, and that MDPC transplantation into cardiomyopathic hearts improves cardiac function. However, the autocrine/paracrine molecules and underlying mechanisms responsible for MDPC growth have not yet been determined. To explore the molecules enhancing the proliferation of MDPCs, we performed serial analysis of gene expression and signal sequence trap methods using RNA isolated from MDPCs. We identified osteopontin (OPN), a secretory molecule, as one of most abundant molecules expressed in MDPCs. OPN provided a proliferative effect for MDPCs. MDPCs treated with OPN showed Akt activation, and inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway repressed the proliferative effect of OPN. Furthermore, OPN-pretreated MDPCs maintained their differentiation potential into endothelial and vascular smooth muscle cells. These findings indicate an important role of OPN as an autocrine/paracrine molecule in regulating the proliferative growth of muscle-derived angiogenic progenitor cells via the PI3K/Akt pathway. (c) 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2007.05.104

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  • Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration

    Kento Tateishi, Eishi Ashihara, Naofumi Takehara, Tetsuya Nomura, Shoken Honsho, Takuo Nakagami, Shigehiro Morikawa, Tomosaburo Takahashi, Tomomi Ueyama, Hiroaki Matsubara, Hidemasa Oh

    JOURNAL OF CELL SCIENCE   120 ( 10 )   1791 - 1800   2007年5月

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    記述言語:英語   出版者・発行元:COMPANY OF BIOLOGISTS LTD  

    Recent studies have shown that cardiac stem cells (CSCs) from the adult mammalian heart can give rise to functional cardiomyocytes; however, the definite surface markers to identify a definitive single entity of CSCs and the molecular mechanisms regulating their growth are so far unknown. Here, we demonstrate a single-cell deposition analysis to isolate individually selected CSCs from adult murine hearts and investigate the signals required for their proliferation and survival. Clonally proliferated CSCs express stem cell antigen-1 (Sca-1) with embryonic stem (ES) cell-like and mesenchymal cell-like characteristics and are associated with telomerase reverse transcriptase (TERT). Using a transgene that expresses a GFP reporter under the control of the TERT promoter, we demonstrated that TERTGFP-positive fractions from the heart were enriched for cells expressing Sca-1. Knockdown of Sca-1 transcripts in CSCs led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing CSC proliferation and survival after direct cellgrafting into ischemic myocardium require Sca-1 to upregulate the secreted paracrine effectors that augment neoangiogenesis and limit cardiac apoptosis. Thus, Sca-1 might be an essential component to promote CSC proliferation and survival to directly facilitate early engraftment, and might indirectly exert the effects on late cardiovascular differentiation after CSC transplantation.

    DOI: 10.1242/jcs.006122

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  • Skeletal myosphere-derived progenitor cell transplantation promotes neovascularization in delta-sarcoglycan knockdown cardiomyopathy

    Tetsuya Nomura, Eishi Ashihara, Kento Tateishi, Satoshi Asada, Tomomi Ueyama, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   352 ( 3 )   668 - 674   2007年1月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Bone marrow cells have been shown to contribute to neovascularization in ischemic hearts, whereas their impaired maturation to restore the delta-sarcoglycan (delta-SG) expression responsible for focal myocardial degeneration limits their utility to treat the pathogenesis of cardiomyopathy. Here, we report the isolation of multipotent progenitor cells from adult skeletal muscle, based on their ability to generate floating-myospheres. Myosphere-derived progenitor cells (MDPCs) are distinguishable from myogenic C2C12 cells and differentiate into vascular smooth muscle cells and mesenchymal progeny. The mutation in the delta-SG has been shown to develop vascular spasm to affect sarcolemma structure causing cardiomyopathy. We originally generated delta-SD knockdown (KD) mice and transplanted MDPCs into the hearts. MDPCs enhanced neoangiogenesis and restored delta-SG expression in impaired vasculatures through trans-differentiation, leading to improvement of cardiac function associated with paracrine effectors secretion. We propose that MDPCs may be the promising progenitor cells in skeletal muscle to treat delta-sarcoglycan complex mutant cardiomyopathy. (c) 2006 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2006.11.097

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  • Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3 beta signaling

    Kento Tateishi, Eishi Ashihara, Shoken Honsho, Naofumi Takehara, Tetsuya Nomura, Tomosaburo Takahashi, Tomomi Ueyama, Masaaki Yamagishi, Hitoshi Yaku, Hiroaki Matsubara, Hidemasa Oh

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   352 ( 3 )   635 - 641   2007年1月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Recent evidence suggested that human cardiac stem cells (hCSCs) may have the clinical application for cardiac repair; however, their characteristics and the regulatory mechanisms of their growth have not been fully investigated. Here, we show the novel property of hCSCs with respect to their origin and tissue distribution in human heart, and demonstrate the signaling pathway that regulates their growth and survival. Telomerase-active hCSCs were predominantly present in the right atrium and outflow tract of the heart (infant &gt; adult) and had a mesenchymal cell-like phenotype. These hCSCs expressed the embryonic stem cell markers and differentiated into cardio-myocytes to support cardiac function when transplanted them into ischemic myocardium. Inhibition of Akt pathway impaired the hCSC proliferation and induced apoptosis, whereas inhibition of glycogen synthase kinase-3 (GSK-3) enhanced their growth and survival. We conclude that hCSCs exhibit mesenchymal features and that Akt/GSK-3 beta may be crucial modulators for hCSC maintenance in human heart. (c) 2006 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2006.11.096

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  • ヒト心筋組織幹細胞研究の現状

    王 英正

    分子血管病   2007年

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  • 心筋細胞の再生医療

    王 英正

    メディカルビューポイント   2007年

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  • Isl-1前駆細胞

    王 英正

    Annual Review 循環器   2007年

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  • 心臓幹細胞移植による臨床応用の可能性

    王 英正

    呼吸と循環   2007年

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  • Single cardiac stem cells exhibit mesenchymal features and require stem cell antigen-1 to proliferate in adult myocardium

    Kento Tateishi, Tomosaburo Takahashi, Tetsuya Nomura, Hiroaki Matsubara, Hidemasa Oh

    CIRCULATION RESEARCH   99 ( 5 )   E20 - E20   2006年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • 心筋再生 : 骨髄由来幹細胞による心筋細胞への可塑性について

    芦原 英司, 王 英正, 松原 弘明

    移植   39 ( 5 )   499 - 508   2004年10月

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  • 難治性虚血性心臓病を細胞移植で再生治療する (第1土曜特集 虚血性心疾患--分子メカニズムの理解から新しい治療へ) -- (新しい治療)

    松原 弘明, 王 英正

    医学のあゆみ   210 ( 6 )   642 - 647   2004年8月

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    記述言語:日本語   出版者・発行元:医歯薬出版  

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    その他リンク: http://search.jamas.or.jp/link/ui/2005050694

  • 心血管前駆細胞と再生医療 : 末梢血管から心臓まで

    松原 弘明, 王 英正, 辰巳 哲也

    呼吸と循環   52 ( 8 )   819 - 825   2004年8月

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    記述言語:日本語   出版者・発行元:医学書院  

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    その他リンク: http://search.jamas.or.jp/link/ui/2004276410

▼全件表示

講演・口頭発表等

  • Cardiosphere-derived cells in congenital heart disease 招待

    Hidemasa Oh

    日本循環器学会総会  2020年8月2日 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 小児心不全に対する再生医療のupdate 招待

    王 英正

    日本再生医療学会  2020年5月18日 

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    記述言語:日本語   会議種別:口頭発表(招待・特別)  

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  • 小児心不全に対する再生医療 招待

    王 英正

    日本心臓病学会学術集会  2019年9月13日 

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    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Clinical Translation of Cell Therapy for Congenital Heart Disease 招待

    王 英正

    国際遺伝子細胞治療シンポジウム  2019年7月22日 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Cell therapy trials in congenital heart disease

    日本遺伝子細胞治療学会  2018年 

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  • Cell Therapy Trials in Congenital Heart Disease

    Pediatric Heart Disease Symposium  2017年 

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  • 心筋組織幹細胞を用いた心筋再生の現状と展望

    CVIT  2017年 

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  • Cell therapy trials in congenital heart disease

    日本遺伝子細胞治療学会  2017年 

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  • 先駆け審査制度での成功事例 自家心臓内幹細胞/小児心不全に対する心筋再生医療法の企業主導多施設共同臨床治験

    AMED シンポジウム 革新的医療技術創出プロジェクト  2017年 

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  • カテーテルによる心筋再生医療について

    日本IVR学会総会  2017年 

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  • Cardiac Progenitor Cell Therapy in Congenital Heart Diseases

    第80回日本循環器学会学術集会  2016年 

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  • Cardiac progenitor cell therapy in congenital heart disease

    American Heart Association  2016年 

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  • 先天性心疾患における心筋再生医療の実用化研究

    第119回小児科学会シンポジウム  2016年 

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  • Cardiac progenitor cell therapy for congenital heart diseases

    3rd Munich Conference on Cardiac Development  2016年 

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  • 心筋再生医療の現状と展望

    Cardiovascular Update 岡山  2015年 

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  • 疾患特異的iPS細胞による新たな先天性心疾患モデルの作成

    小児循環器学会  2015年 

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  • 小児心不全に対する心筋再生医療法の企業主導多施設共同臨床治験

    橋渡し研究シンポジウム  2015年 

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  • 心不全に対する細胞治療法の実用化と医工学融合した次世代心筋再生医療法の開発

    岡山先端医学研究会  2015年 

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  • 小児心不全に対する心臓内自己幹細胞移植治療の標準医療化に向けた取り組み

    小児循環器学会  2015年 

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  • 心臓内幹細胞を用いた先天性心疾患の病態解明と再生医療

    ミニリトリート 徳島  2015年 

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  • 子どもの心臓病に再生医療は有効か?

    岡山大学公開講座  2015年 

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  • 心臓内幹細胞を用いた小児心疾患の解明と再生医療

    第34回日本小児病理研究会学術集会  2014年 

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  • 心臓内幹細胞を用いた小児心疾患の解明と再生医療

    高知小児循環器・川崎病研究会  2014年 

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  • 臨床試験における具体的な評価指標の定め方

    技術情報協会セミナー  2014年 

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  • 小児心不全に対する心臓内幹細胞自家移植療法の第I/II相臨床研究

    第56回日本小児血液・がん学会学術集会  2014年 

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  • 先天性心疾患への再生医療の現状

    抗加齢医学会総会  2014年 

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  • 左心低形成症候群に対する心筋再生医療の第1/2相臨床研究

    日本小児循環器学会  2014年 

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  • iPS細胞を用いた左心低形成症候群における疾患発症機序の解明

    日本小児循環器学会  2014年 

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  • Intracoronary delivery of cardiac progenitor cells in patients with hypoplastic left heart syndrome.

    The 30th International Society for Heart Research  2013年 

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  • 希少難治性心不全に対するヒト幹細胞移植療法の長期的エビデンス

    第12回日本再生医療学会  2013年 

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  • 疾患特異的幹細胞およびiPS細胞を駆使した希少小児心疾患に対する細胞治療と病態解明

    消化器研究セミナー  2013年 

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  • iPS細胞を用いた心疾患の新たな診断法と治療開発

    岡山大学サイエンスカフェ  2013年 

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  • 子どもの難治性心不全に対する幹細胞移植療法の取り組み

    公開セミナーはあとネット兵庫  2013年 

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  • 希少難治性心不全に対する心臓内幹細胞を用いた再生医療

    青森臨床循環器研究会  2013年 

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  • 希少難治性心不全に対する心臓内幹細胞を用いた再生医療

    岡山大学知恵の見本市2013  2013年 

     詳細を見る

  • 心不全への幹細胞移植療法

    岡山先端医学研究会  2013年 

     詳細を見る

  • 心不全への幹細胞移植療法

    第3回先端医学研究会at OU  2013年 

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  • 先天性心疾患に対する自己心臓内幹細胞による再生医療

    第116回日本小児科学会学術集会  2013年 

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  • Mechanical stretch promotes reprogramming of human cardiac progenitors into functional cardiomyocytes by defined factors.

    日本循環器学会  2012年 

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  • 心筋再生医療の臨床試験と研究開発状況

    技術情報協会セミナー  2012年 

     詳細を見る

  • Cardiac progenitor cell infusion in patients with hypoplastic left heart syndrome: a prospective phase 1 clinical trial

    Japanese Heart Failure Society  2012年 

     詳細を見る

  • 重度心臓病に対する心筋再生医療

    オープンフォーラム2012 岡山  2012年 

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  • Mending and Modeling the Congenital Heart Diseases by Patient-Specific Cardiac Progenitors.

    Symposium at Texas Heart Institute  2012年 

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  • 小児心不全への再生医療の可能性

    第15回遺伝子治療推進産学懇話会  2012年 

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  • Mending and Modeling the Congenital Heart Diseases by Patient-Specific Cardiac Progenitors

    東京女子医科大学セミナー  2012年 

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  • 左心低形成症候群に対する心臓内幹細胞自家移植療法

    第7回岡山心移植心不全研究会  2012年 

     詳細を見る

  • 小児心不全と細胞治療

    先天性心疾患シンポジウム  2012年 

     詳細を見る

  • 小児心不全に対する細胞治療の中間報告と疾患特異的iPS細胞の樹立による次世代心臓再生法の開発

    橋渡し研究加速推進ネットワークシンポジウム  2012年 

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  • 先天性心疾患患者由来の心臓内幹細胞を用いた疾患特異的ヒトiPS細胞の樹立と機能解析.

    日本小循環器学会  2012年 

     詳細を見る

  • Heterokaryon-based reprogramming of human cardiac progenitor cells into functional cardiomyocytes.

    日本小循環器学会  2012年 

     詳細を見る

  • Mechanical stretch modulates calcium handling during direct cardiac reprogramming of resident progenitor cells in human heart.

    国際幹細胞学会  2012年 

     詳細を見る

  • Transition of cardiogenic to angiogeneic potential of human cardiac progenitor cells occurs with age.

    国際幹細胞学会  2012年 

     詳細を見る

  • Patient-specific induced pluripotent stem cells from cardiac progenitors recapitulate the models for cardiac chamber disorders.

    欧州心臓病学会  2012年 

     詳細を見る

  • Mechanical stretch modulates calcium handling during direct cardiac reprogramming of resident progenitor cells in human heart.

    欧州心臓病学会  2012年 

     詳細を見る

  • 小児心不全に対する細胞治療の中間報告と疾患特異的iPS細胞の樹立による次世代心臓再生法の開発

    橋渡し研究加速推進ネットワークシンポジウム  2012年 

     詳細を見る

  • 小児心不全への細胞治療法の可能性

    岡山心臓血管外科カンファレンス  2012年 

     詳細を見る

  • Mending and Modeling the Congenital Heart Diseases by Patient-Specific Cardiac Progenitors

    2012年 

     詳細を見る

  • Patient-specific induced pluripotent stem cells from cardiac progenitors recapitulate the models for cardiac chamber disorder.

    国際幹細胞学会  2012年 

     詳細を見る

  • Reprogramming of human cardiac progenitors into pluripotency in patients with congenital heart disease.

    日本循環器学会  2012年 

     詳細を見る

  • 小児心不全と細胞治療

    先天性心疾患シンポジウム  2012年 

     詳細を見る

  • 心不全の心筋再生医療

    岡二会  2012年 

     詳細を見る

  • Insulin-like growth factor-2 receptor controls human cardiac progenitor proliferation and differentiation in children with congenital heart malformation.

    米国心臓病学会  2011年 

     詳細を見る

  • 小児心不全への細胞治療の現状と展望

    重症心不全治療フォーラム  2011年 

     詳細を見る

  • Direct induction of human cardiac progenitor cells to functional cardiomyocytes by defined factors.

    米国心臓病学会  2011年 

     詳細を見る

  • Heterokaryon-based reprogramming of human cardiac progenitor cells into functional cardiomyocytes.

    日本胸部外科学会  2011年 

     詳細を見る

  • Direct reprogramming of human cardiac progenitor cells towards functional cardiomyocytes.

    日本胸部外科学会  2011年 

     詳細を見る

  • Generation and functional analysis of induced pluripotent stem cells in patients with congenital heart disease.

    日本胸部外科学会  2011年 

     詳細を見る

▼全件表示

Works(作品等)

  • 2012見本市

    2012年

     詳細を見る

    作品分類:芸術活動  

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受賞

  • 文部科学大臣表彰科学技術賞

    2012年4月  

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    受賞国:日本国

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  • 文部科学大臣表彰若手科学者賞

    2005年4月  

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共同研究・競争的資金等の研究

  • RNA誘導型遺伝子編集幹細胞による多様性免疫細胞を標的とした組織修復再生法の開発

    2021年04月 - 2022年03月

    国立研究開発法人日本医療研究開発機構  橋渡し研究戦略的推進プログラム(シーズA) 

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    担当区分:研究代表者 

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  • 輸送幹細胞の肺組織内集積反応により遊出される心筋再生促進因子の同定と実用化研究

    研究課題/領域番号:19H03738  2019年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    王 英正

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    配分額:17420000円 ( 直接経費:13400000円 、 間接経費:4020000円 )

    本研究では、移植した細胞のうち最もロッジする近接臓器である肺組織自身を介したparacrine効果の検討が目的であり、我々が報告してきたIGF-1やHGF以外の新たな心筋再生促進因子を同定する研究計画である。
    1. 新たな手術法により確立したラットおよびブタ単心室循環モデルに対する心臓内幹細胞の経静脈的注入法による生命予後改善効果の検討ー単心室循環モデルに対する細胞移植において、急激な低酸素状況への暴露による生体内環境変化のため、非移植群に対する細胞移植の有意な生存率の改善効果は認めなかった。
    2. 正常の2心室心ならびに単心室心のラットに、培地もしくは1.0x106/kg個の心臓内幹細胞を静脈内に注入後12時間目に心臓と肺組織を採取し、Agilent Array発現解析による網羅的遺伝子検索を行うー正常心への幹細胞静脈内注入後の組織解析において、肺特異的な遺伝子上昇群を6因子同定した。
    3. Real-Time RT-PCR法を用いて、正常心で培地もしくは細胞移植で有意に変化した遺伝子群を抽出し、この候補因子群に対して、2次スクリーニングとして単心室心モデルにおいても同様に有意な変化を示した遺伝子群に最終的に絞るー上記候補因子群のうち、リアルタイムの遺伝子解析において、単心室モデルにおいても重複して有意な上昇を示した遺伝子群は3つあり、一つは従来より報告されているTNF-alphaの活性化上昇に伴い代償的に阻害する因子の一つであるTSG6を含んでいた。

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  • 腸管スキャフォールドとコラーゲン結合型成長因子を用いた拍動性グラフトの創成

    研究課題/領域番号:18K08759  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    笠原 真悟, 松下 治, 王 英正, 美間 健彦

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    組織工学を用いた臓器再生研究の分野で、脱細胞化した心臓に心筋細胞を移植する
    ことで拍動が得られることが報告された。また、脱細胞化した腸管を組織工学の鋳型として利用できることも報告された。これまでに我々は、細菌性コラゲナーゼのコラーゲン・アンカー部を用いて結合組織やコラーゲン基剤に成長因子をアンカリングすることで、その効果を持続的に発揮させられることを示した。
    2019年度は、ラット小腸を腸間膜動静脈を含め脱細胞化して足場とし、心筋細胞の増殖と血管新生を誘導する種々の成長因子をアンカリングしつつ、ラット新生児の心臓由来細胞を播種することで、栄養血管を備えた拍動する心筋の筒を作製しようと考えていた。
    まずラット小腸の脱細胞化を試みた。生体から小腸を採取し、動静脈にカニュレーションし、界面活性剤を24から48時間程度還流することにより脱細胞化できることを確認した。続いて、脱細胞化した小腸の細胞外マトリックスを足場として、心筋細胞を生着させようと試みた。従来我々が用いていた解放空間における灌流装置で、脱細胞化小腸にラット新生児心筋細胞を付着させ培養液を還流したが、良好な成育は認められなかった。心筋の破砕の程度、還流流量などを変化させたが、十分な生着といえる成果は得られなかった。そこで、温度、湿度、CO2濃度を管理できるインキュベータ内で培養すべく、小型の還流装置を試作した。しかしながら最適な還流量の確立が困難で、現在足場素材、大きさの再検討、それに対する流量の検討を進めている。

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  • 心臓内幹細胞移植による小児拡張型心筋症に対する再生医療の臨床研究

    2016年04月 - 2019年03月

    国立研究開発法人日本医療研究開発機構  再生医療実用化研究事業 

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    担当区分:研究代表者 

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  • エクスプラント心由来の自己幹細胞移植による拒絶緩和と膜組織作成法の開発

    研究課題/領域番号:15K10216  2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    新井 禎彦, 王 英正

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    純系ラットを用いた異所性心移植慢性期生存モデルによる自己幹細胞移植評価を実施した。その結果細胞投与群は細胞非投与群に比較してグラフト生着期間の延長と心機能の改善傾向がみられ現在統計学的解析などの評価を行っている。さらに移植心内の細胞由来を追跡調査した。これにより、心機能の改善が幹細胞由来細胞生着と増殖によるものか、いわゆるパラクリン作用による移植心の細胞の増殖、機能改善によるものかを特定することを目指している。現状ではその混在の割合が圧倒的優位性を持っている状態とは言い難いため、作用機序特定のためには多様な内分泌、化学的伝達物質などの評価を要する可能性がある。

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  • Ex-vivo Heart Perfusionを用いた心臓移植の臨床応用

    研究課題/領域番号:15K10215  2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小谷 恭弘, 王 英正

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    現在、心臓移植のドナーとなりうるのは脳死に陥った患者様(脳死ドナー)であるが、その発生頻度は少なくドナー不足が問題となっている。代替として心停止を起こした患者様がドナーとなる場合(心停止ドナー)があるが、心臓は脳死や心停止になった際に同時に障害を受けてしまい、心臓が臓器移植に耐えうるかどうか不明であるという問題がある。本研究では、心停止ドナーからの心臓移植の実現を目指して、どのように心臓を保護すれば、一度心停止になった心臓が蘇生されるかを調べた。結果として、適切な心筋への血液や酸素の供給(調節再還流)を行うことで、心停止前と同等の心臓の機能まで回復することが示された。

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  • 小児心不全に対する心筋再生医療法の企業主導多施設共同臨床治験

    2015年04月 - 2018年03月

    国立研究開発法人日本医療研究開発機構  革新的医療技術創出拠点プロジェクト (シーズC) 

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    担当区分:研究代表者 

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  • メカノメディスン:メカノ医工学を駆使した再生医療・生殖医療への展開

    研究課題/領域番号:26220203  2014年05月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(S)  基盤研究(S)

    成瀬 恵治, 王 英正, 高橋 賢, 松浦 宏治, 入部 玄太郎

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    配分額:201760000円 ( 直接経費:155200000円 、 間接経費:46560000円 )

    メカノ心臓再生医療に関し、ヒトiPS細胞から自発的に収縮する心筋細胞への分化誘導を行った。この分化誘導は周期的伸展刺激により早期化し、ヒト線維芽細胞との共培養により促進された。小児拡張型心筋症に対する心臓内幹細胞の自家移植療法に関し、TICAP-DCM第1相臨床研究を3症例に対し行い、細胞移植を無事に実施した。
    メカノ生殖補助医療に関し、マウス受精卵を用いてメカニカルストレスの有無による遺伝子発現の違いを網羅的解析したところ、胚発育、細胞死、環境ストレス等に関する遺伝子発現に有意差が見られた。また従来のマウス用チャンバーに対し、ヒト受精卵に利用可能な高純度シリコン樹脂製チャンバーを完成させた。

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  • 心疾患治療に向けた革新的次世代メカノ組織工学・再生医療の創生

    研究課題/領域番号:26242042  2014年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    成瀬 恵治, 王 英正, 高橋 賢, 入部 玄太郎

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    配分額:23270000円 ( 直接経費:17900000円 、 間接経費:5370000円 )

    心臓再生医療において、力学的・機械的刺激(メカニカルストレス)を用いた新しい技術を開発するために研究活動を行った。まず、心臓機能障害の動物モデルを作出するためにin vivoでECGを記録しつつラット冠状動脈左前下行枝(LAD)を結紮する実験を行った。組織学的解析の結果、LAD支配領域に心筋壊死による梗塞巣が形成されていることが確認された。計画段階において、心機能障害のモデルとして心筋梗塞モデルと右心不全モデルの作出を想定していたが、心筋梗塞モデルの作出は達成された。
    細胞培養による移植細胞の作出実験に関しては、3次元培養用の培養装置の開発を行い、これを用いた細胞培養を開始した。新生児ラットの単離心筋細胞およびラット心筋細胞株を用いた実験により、ゲルを足場にして細胞が3次元的に生育あるいは増殖することを確認した。この成果により、ずり応力およびストレッチによる機械的刺激を細胞に負荷する環境が確立された。
    またOxford大学客員教授のPeter Kohlを招聘し、メカニカルストレスによる心臓再生医療の開発に関しディスカッションを行った。さらにメカノバイオロジーの世界的な権威が集う国際学会International Symposium on Mechanobiology 2014に研究者を参加させ、関連研究領域の情報収集を行った。また3次元プリンタのワークショップにも研究者を参加させ、細胞培養用の培養器開発の実務的知見を取得させた。
    本研究の内容を包括する基盤研究(S)「メカノメディスン:メカノ医工学を駆使した再生医療・生殖医療への展開」の交付決定に伴い、本研究課題を終了しこれに引き継ぐこととした。

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  • 小児心不全に対するヒト幹細胞移植による先進医療の実用化加速に向けた第2相臨床研究

    2013年04月 - 2016年03月

    厚生労働科学研究費補助金  再生医療実用化研究事業 

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    担当区分:研究代表者 

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  • ヒト人工心筋細胞の純化精製と機能的心臓の三次元再構築

    研究課題/領域番号:25670389  2013年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    王 英正

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    本研究では、ヒト心臓内幹細胞とラット心筋細胞の細胞間融合を介した人工心筋細胞の大量精製後、ラット全心臓の脱細胞化による細胞外マトリックスで形成された足場の作成をした。脱細胞化した心臓への人工ヒト心筋細胞およびヒト心血管前駆細胞の再播種化することで、再構築した自家細胞由来バイオ人工心臓の機能解析及び移植検討した。細胞は5x107個の精製したヒト人工心筋細胞と5x107個のヒト心臓内幹細胞をPBSに希釈し、27ゲージの針使用し5回に分けて左心室内に注入する。回路内を密閉後、約8から10日間持続潅流させることで三次元培養を行い、全周性で均一な生存心血管細胞で覆われた心臓器官の形成に成功した。

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  • 希少難治性心疾患由来iPS細胞を用いた左心低形成症候群の予後因子の解明に関する研究

    2013年04月 - 2014年03月

    厚生労働科学研究費補助金  難治性疾患等克服研究事業 

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    担当区分:研究代表者 

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  • 脱細胞化したマトリックスへのヒト人工心筋細胞の再播種によるバイオ人工心臓の作成

    研究課題/領域番号:23659672  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    佐野 俊二, 王 英正

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    心臓移植の事業推進において臓器提供者不足が大きな問題であり、次世代の臓器移植医療法の開発が必要である。摘出心臓をランゲンドルフ潅流装置用いて脱細胞化させることで立体的な足場を形成し、周期的な前後負荷及び電気刺激を与えつつ、ヒト心臓内細胞及び血管内皮細胞を潅流培養させることで、冠動脈血流を伴い、緻密に作業心筋細胞が生着することで、より高い機能性のある自家細胞由来の心臓としての器官形成に成功した。

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  • 異種間ヘテロカリオン細胞の包括的遺伝子解析によるヒト心筋細胞初期変換因子群の確立

    研究課題/領域番号:23659419  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    王 英正

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    ヒト細胞における心筋細胞への直接誘導因子群は明らかでなく、本研究において、ヒト心筋前駆細胞とマウス成熟心筋細胞との異種間細胞融合法を用いてヘテロカリオン細胞を作製し、本質的な心筋細胞への再プログラム化因子群を同定した。本研究により、従来のGATA4, Mef2c, Tbx5に加え、Myocardin, Hand2といった複合的な制御転写因子群が必須であり、合計5因子群による心筋前駆細胞から直接心筋細胞への形質変換法の確立に成功した。

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  • 小児心不全に対する細胞治療と単心室症由来人工多能性幹(iPS)細胞の樹立による次世代心筋再生医療法の開発

    2010年04月 - 2013年03月

    厚生労働科学研究費補助金  成育疾患克服等次世代育成基盤研究事業 

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    担当区分:研究代表者 

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  • ヒト心臓内多能性幹細胞と幹細胞増幅因子bFGF徐放シートのハイブリッド移植療法による心筋再生医療の多施設共同型臨床研究

    2008年04月 - 2011年03月

    厚生労働科学研究費補助金  再生医療実用化研究事業 

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    担当区分:研究分担者 

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  • 新たな幹細胞増幅因子とヒト心臓内幹細胞を併用した心不全への自家細胞移植療法の開発

    研究課題/領域番号:20390223  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    王 英正

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    配分額:19110000円 ( 直接経費:14700000円 、 間接経費:4410000円 )

    重度の虚血性心不全に対して、自己心臓内幹細胞の心筋内注入に加え、幹細胞増殖促進因子の一つである塩基性線維芽細胞増殖因子(bFGF)を併用した細胞治療法を開発することに成功した。慢性心筋梗塞のミニブタにおける免疫機能を抑制下、ヒト心臓内幹細胞の心筋内注入とbFGFの組織内徐放を併用した細胞治療法の前臨床試験を行った。本法による治療後、左室駆出率と心筋局所壁運動は有意に改善し、心筋梗塞サイズは著明に縮小した。

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  • Cre-loxPシステムを用いたAkt依存性に活性化される心筋細胞再生因子の単離

    研究課題/領域番号:19659204  2007年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    王 英正, 上山 知己, 小形 岳寛

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    配分額:3300000円 ( 直接経費:3300000円 )

    本研究の目的は、心臓内幹細胞の特異的増殖規定因子の同定であり、これまでの我々の報告から、心臓内幹細胞は主として、細胞表面抗原であるSca-1で認識及び精製できること、また、Sca-1ノックダウンマウスの機能解析から、Aktが重要な候補支配因子であることが明らかとなった。そこで、本研究では、Sca-1プロモーターにAktをノックインした薬剤誘導型Akt発現マウス(Sca-1/Akt mice)を作成し、遺伝子工学的手法用いて、Akt依存性に活性化される心臓内幹細胞の網羅的検索を行った。結果:1)Sca-1ノックダウンマウスに急性虚血を作成すると、梗塞後1週間での生存率が約30%と野生型の70%に比べ、有意に低下したことから、Sca-1依存性に心臓内幹細胞の自己増殖に重要な因子の発現低下が関与していることが示唆された。一方、Sca-1/Akt miceに虚血を導入すると、急性生存率が野生型と同様なレベルまでに回復し、Sca-1/Aktの活性化を軸とした心臓内幹細胞による障害心筋細胞の自己修復機構の存在が確認された。2)Sca-1/Aktを介した心臓内幹細胞の増殖規定因子を検索するため、野生型及びSca-1/Aktマウスの心臓内から幹細胞をそれぞれ精製し、マイクロアレイによる網羅的検索を行った。cutoff indexを2倍以上に上昇した因子群に集約すると、心臓幹細胞はAkt依存性に活性化される増殖制御因子として、インスリン様成長因子結合蛋白4やセマフォリン3C、さらに、Wnt/beta-cateninの経路を調節するfrizzled関連蛋白1/2が候補因子として同定された。これらの因子群はいずれもin vitroでの検討で心臓内幹細胞の増殖能を促進させ、今後in vivoにおけるこれらの因子群の心筋虚血耐性の役割について、さらに詳細に検討していく予定である。

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  • Expression cloning法による心筋細胞分化制御因子の同定と機能解析

    研究課題/領域番号:18590773  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    上山 知己, 松原 弘明, 王 英正, 原田 光一郎, 小形 岳寛

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    配分額:3890000円 ( 直接経費:3500000円 、 間接経費:390000円 )

    心筋細胞分化の分子機序の解明と、選択的にES細胞を心筋細胞へと分化制御する因子の同定とその機能解析を目的に以下の研究を行った。
    1.cDNAライブラリーを発現する非増殖性組み換えレトロウイルスの作製。
    P19CL6細胞を用い心筋細胞への分化誘導を行い、分化誘導後4〜7日の細胞より抽出したmRNAからcDNAを合成し、レトロウイルスベクターに組み込みcDNAライブラリーを作製し、非増殖性組み換えレトロウイルスを作製した。
    2.未分化状態のES細胞を分化誘導する因子の探索。
    心筋細胞へと分化するとGFP遺伝子を発現するES細胞を用い、作製したcDNAライブラリーをレトロウイルスベクターにより遺伝子導入し、心筋細胞へと分化しGFPを発現した細胞群より染色体DNAを抽出した。その染色体DNAを用い、レトロウイルスベクターを認識するベクタープライマーを用いたPCRによりcDNAを回収し、その塩基配列をシークエンサーにより決定し、G protein beta polypeptide 2 like 1(Gnb211,Rack1),oxidase assembly 1-like(0xa11),glutaredoxin 5 homolog(Glrx5),aurora kinase A interacting protein 1(Aurkaipl)などを候補遺伝子として得た。
    3.同定した候補遺伝子の機能解析。
    同定した候補遺伝子のfull-length cDNAをレトロウイルスベクターによりES細胞に発現させることにより、これらの遺伝子の心筋細胞への分化誘導能を検討しており、本研究を進めることにより、心筋細胞分化の分子機序の解明と、選択的に心筋細胞に分化誘導する方法の開発につながると考える。

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  • ヒト心筋幹細胞移植療法の前臨床的確立と細胞組織工学によるハイブリッド療法の開発

    研究課題/領域番号:18390233  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    王 英正, 上山 知己, 原田 光一郎, 小形 岳寛

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    配分額:17050000円 ( 直接経費:15700000円 、 間接経費:1350000円 )

    ヒト心臓内幹細胞と幹細胞増幅因子を統合した心筋再生医療法の前臨床的確立に向けて、以下の2つの課題を明らかにした。1)幹細胞増幅因子の同定-activinII型受容体拮抗薬であるfollistatinは骨格筋組織幹細胞において、幹細胞コロニーの自己増殖能を増加させる作用があることを確認した。activinII型受容体を介するTGF-beta familyのリガンドを特定するため、myostatin欠損マウスの骨格筋組織より精製した心筋幹細胞の増幅動態を培養細胞系で検討。骨格筋組織幹細胞は骨格筋芽細胞と異なり、myostatinの情報伝達を介さず、むしろ、GDF11やactivin Aによる幹細胞の増幅調節を受けていることが明らかとなった。一方、心臓内幹細胞の自己増幅因子は幹細胞の認識抗原であるSca-1のノックダウンマウスを用いた検討で、bFGF/Aktを中心とする情報伝達が幹細胞の増幅過程を制御していることが確認された。2)ヒト心臓内幹細胞移植と幹細胞増幅因子の併用療法の安全性と有効性の検証一大型動物を用いてのランダム割り振り前臨床治験を行った。慢性心筋梗塞モデルを作成し、研究目的1)で確認したbFGFを生体吸収材料であるゲラチンハイドロゲル用いて、心筋組織内に徐放し、免疫抑制下でヒト心臓内幹細胞を移植した。心エコー検査や心臓MRIによる心機能評価では、bFGFによる心筋微小血流の改善に伴い、細胞周囲環境が調節され、ヒト心臓内幹細胞移植の生着性が、通常の幹細胞単独移植に比べ2倍以上、さらにin vivoでの心筋細胞再生能が8倍以上と有意に向上した。本研究により、心臓内幹細胞とbFGFのハイブリッド療法は最も有効な心機能改善と実質的な心筋細胞再生をもたらす画期的な再生医療法として確立した。

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  • 胚性幹細胞との細胞融合及び遺伝子工学的手法で再プログラムされた心筋幹細胞株の樹立

    研究課題/領域番号:18659224  2006年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    王 英正, 上山 知己, 原田 光一郎, 小形 岳寛

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    配分額:3300000円 ( 直接経費:3300000円 )

    増幅能が限られている体性幹細はテロメア関連伝子導入によって不死化する試みがされているが、遺伝子をベースにした方法では常に悪性腫瘍化する危険性が付きまとう。そこで、申請者らはES細胞との細胞融合によって、ES細胞が持つ極めて高い増殖性の性質を申請者らが単離に成功した心筋幹細胞に形質伝承する目的で、Cre-loxPシステムを利用したレトロウイルスベクターを作成した。ES細胞と融合によって形質変換した細胞の精製によって、心筋幹細胞クローンにCre-IRES-RFPレトロウイルスを感染させ、ウイルス感染が良好であることを確認した。
    (1)puro/hygroの抗生剤選択で純化したハイブリッド細胞が4倍体であることをFACSで確認した。融合した心筋細胞は免疫組織染色にて、心筋幹細胞には発現していないES細胞特異的な転写因子の提示を認め、細胞融合の効率がその後の解析に有効な頻度(約50%)で生じていることを検証した。
    (2)RNAを回収しマイクロアレイによる網羅的検索によって、未分化ES細胞特異的転写因子や細胞周期調節因子について網羅的検索を行ったところ、約6割の心筋幹細胞特異的遺伝子の発現減少とそれに伴うES細胞固有因子の増加を融合した新規細胞の遺伝子プロファイルにて確認した。このことは、細胞融合によって心筋幹細胞が完全に形質変換したことを直接証明するものではなく、細胞融合前の約6割の心筋幹細胞がES細胞との再プログラムによる修飾の影響を受けたことを強く示唆した。
    (3)neo耐性遺伝子を持つalpha-MHC-EGFPを導入したES細胞の形質を継承した再プログラムされた心筋幹細胞は、in vitroにて通常のES細胞に比べ、心筋細胞に分化する効率が約3倍向上したことをEGFPの発現頻度にて確認された。逆に融合した心筋幹細胞は正常のES細胞と比し、細胞増殖能が約半分に低下した。このことは、ES細胞の持つ多能性分化能を再プログラムする手法を用いて、遺伝子工学的に幹細胞の運命を制御したことを証明し、今後の虚血心への融合細胞移植実験にて、生体内での心筋細胞再生医療への有用性について研究を発展させていく予定である。

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  • ヒト心筋・骨格筋からの心筋幹細胞株の樹立と末期的心不全への幹細胞移植医療実現化へ向けての研究基盤形成

    2005年04月 - 2008年03月

    厚生労働科学研究費補助金  医療技術実用化総合研究事業  基礎研究成果の臨床応用推進事業

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    担当区分:研究分担者 

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  • ヒト心筋・骨格筋からの心筋幹細胞株の樹立と末期的心不全への幹細胞移植医療の実現化-ES細胞からの心筋前駆細胞クローン単離と不死化・増幅-

    研究課題/領域番号:17209028  2005年 - 2007年

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    松原 弘明, 高橋 知三郎, 王 英正, 辰巳 哲也

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    配分額:49530000円 ( 直接経費:38100000円 、 間接経費:11430000円 )

    申請者らは、細胞移植療法の実現化に向けて、効率よく短期間内で心筋幹細胞の大量増幅を行う目的で、遺伝子工学的手法を用い、幹細胞特異的増幅因子の同定及び機能解析を行った。心筋幹細胞を認識する表面抗原Sca-1に注目し、Sca-1ノックダウンマウスを作成し解析した結果、心筋幹細胞はbFGF依存性にAktの活性化を介して、生体内における幹細胞の増殖及び細胞移植後の生着促進に重要であることを突き止めた。同様の培養技術を用いて、ヒト心臓生検組織からの心筋幹細胞の単離・増幅技術を確立し、また、この心筋幹細胞の特異的増殖・維持因子がbFGFであることを初めて明らかにした。現在、世界初の実質的な心筋細胞分化を伴う細胞移植再生医療の実現化に向けて、ヒト心筋幹細胞移植とその増幅因子を組み合わせたハイブリッド療法(bFGF徐放生体吸収シート)の前臨床治験を進めている。本研究は幹細胞単独移植でなく、bFGF徐放生体吸収シートを組み合わせたハイブリッド療法であることが大きな特徴であり、臨床治験に向けたブタ陳旧性心筋梗塞モデルを用いたランダム割り振り前臨床治験を6カ月前から実施している。左冠動脈をバルーンで閉塞後解放して作成した雌ブタ心筋梗塞部に1月後に免疫抑制薬の投与とともに、男性ヒト心筋幹細胞移植とbFGF徐放生体吸収シート貼りを併用する。MRIでさらに1月後の心臓機能を解析すると、bFGF徐放生体吸収シートだけでは3-4%の改善であったが、心筋幹細胞移植との併用では12%もの改善が見られている。移植部位では細胞融合を伴う、移植細胞による心筋分化が豊富に見られていた。また、移植細胞はbFGF徐放生体吸収シートの存在により1月後には移植部位において、30%の生着が観察された(シートなしでは5%生着)。本研究は幹細胞単独移植でなく、bFGF徐放生体吸収シートを組み合わせたハイブリッド療法であることが大きな特徴であり、臨床治験に向けたブタ陳旧性心筋梗塞モデルを用いたランダム割り振り前臨床治験は世界でも行われておらず、非常に心機能改善効果の高い心筋再生治療と期待される。

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  • 心筋幹細胞移植医療の実現化に向けたヒト心筋幹細胞特異的増幅因子のクローニング

    研究課題/領域番号:17659233  2005年 - 2006年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    王 英正

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    配分額:3400000円 ( 直接経費:3400000円 )

    平成17年7月1日より、心筋幹細胞移植医療の実現化に向けたヒト心筋幹細胞特異的増殖因子のクローニングに関する研究課題に関し、特にsignal sequence trap法を使ったadult由来心筋幹細胞の増殖因子の同定に関する研究を開始した。
    採取したadult由来マウス心筋幹細胞からのcDNA library作製し、レトロウイルスパッケージング細胞であるPlatE細胞にRoche社のFuGENE6を使用して導入し、レトロウイルスとして回収した。回収したレトロウイルスを感染効率が20%弱になるように調整してBa/F3細胞に感染させ、96well plateに10000個/wellで撒き、IL-3非存在下で2週間程培養した。培養により、シグナル配列を持たないpMX-SSTが感染したBa/F3細胞は死滅し、シグナル配列を持ったcDNA断片を融合したpMX-SSTが感染したBa/F3細胞のみ増殖が認められ、最終的に200近くの細胞クローンが認められた。これらの細胞クローンから染色体DNAを抽出した後、vector primerを用いてPCRを行い、挿入cDNA断片を回収した。
    回収したcDNA断片のすべてに対してシーケンサーによる解読を行い、NCBI BLASTホームページ上のnucleotide-nucleotide blastを使って相同性検索を行ったところ、adult由来マウス心筋幹細胞に特異的に発現している分泌タンパク質が2つ認められた。この2つは、RT-PCRでもmRNA発現が亢進していることを確認し、そのうちの1つは免疫染色でsphereを形成している細胞上に強くタンパク発現していることも確認した。
    現在、これらの同定されたタンパク質についてrecombinantによる薬物的刺激実験とノックアウトマウスを使った抑制実験の2つの方向から、同定されたタンパク質のマウス心筋幹細胞への増殖に対する効果を解析すべく準備を進めている。今後、同定されたタンパク質が増殖に関わることが明らかになれば、ヒト心筋幹細胞への応用が可能かどうか検討していく予定である。

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  • 新たに同定した心臓由来心筋前駆細胞のクローン化増殖、機能解析による心筋再生医療

    研究課題/領域番号:16689017  2004年 - 2006年

    日本学術振興会  科学研究費助成事業 若手研究(A)  若手研究(A)

    王 英正

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    配分額:28470000円 ( 直接経費:21900000円 、 間接経費:6570000円 )

    心臓由来の心筋前駆細胞の細胞機能解析として、平成16年度に引き続き、平成17年度一年間で以下の2つの課題を明らかにしてきました。
    1)心臓由来のSca-1陽性細胞のクローン化とその多能性を明らかにすること。
    平成16年度の報告のように、申請者らは心筋前駆細胞である心臓由来のSca-1陽性細胞を単一細胞より大量増幅させ、そのクローン化に成功した。各クローンはそれぞれ心筋細胞に分化できるポテンシャルが異なり、心筋細胞以外では血管平滑筋、内皮、グリア、脂肪、上皮細胞への多能性分化能についても確認しえた。
    2)マウス生体内でのSca-1遺伝子の役割をSca-1欠損マウスへ心筋梗塞作成することで明らかにする。
    平成16年度内にSca-1ノックダウンマウスの作成に成功した。ある一定の数まで動物を繁殖させた後、マウスの表現型の解析を開始した。Sca-1ノックダウンマウスは生後異常なく成長し、心臓にも異常が認められなかった。しかしながら、Sca-1ノックダウンマウスより精製純化した心筋幹細胞コロニーは増幅能を著しく傷害され、野生型の心筋幹細胞と比べ、長期培養は不可能であった。また、Sca-1ノックダウンマウス由来の心筋幹細胞は高い増幅能を持った細胞に特徴的なテロメラーゼ活性も著しく低下し、細胞周期調節因子であるp53の発現上昇を認めた。興味深いことに、Sca-1ノックダウンした心筋幹細胞をドナーとして用い、虚血心に細胞した場合、野生型の細胞移植と比べ、心筋細胞の再生能及び心機能改善効果は著しく障害を受けた。また、Sca-1ノックダウンマウスに心筋梗塞を作成すると、梗塞巣が繊維化領域の拡大により、野生型と比べ増加し、1ヶ月目までの虚血心マウスの生存は有意に低下した。これらのことより、Sca-1は心筋幹細胞を認識するだけでなく、心臓内心筋幹細胞の自己増幅能を制御する重要な因子であることが示唆された。

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