研究者詳細 - 王　英正

論文 - 王　英正

分割表示 >> ／全件表示 52 件中 1 - 52 件目

Eight‐Year Outcomes of Cardiosphere‐Derived Cells in Single Ventricle Congenital Heart Disease 査読

Kenta Hirai, Ryusuke Sawada, Tomohiro Hayashi, Toru Araki, Naomi Nakagawa, Maiko Kondo, Kenji Yasuda, Takuya Hirata, Tomoyuki Sato, Yuki Nakatsuka, Michihiro Yoshida, Shingo Kasahara, Kenji Baba, Hidemasa Oh

13 ( 22 ) e038137 2024年11月

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

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

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

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

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

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

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

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

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

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

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

Cell Therapy Trials in Congenital Heart Disease. 国際誌

Hidemasa Oh

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

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

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

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

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

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

機能的単心室における冠動脈バルーン閉鎖下心筋幹細胞注入の実際

栄徳隆裕, 馬場健児, 近藤麻衣子, 栗田佳彦, 福嶋遥佑, 平井健太, 大月審一, 石上修大, 佐野俊二, 王英正

Journal of JPIC 1 ( 1 ) 13 - 19 2016年8月

記述言語：日本語出版者・発行元：(一社)日本先天性心疾患インターベンション学会

背景:心筋再生医療は,成人を対象としたものがほとんどで小児を対象とした臨床研究は極めて少ない.また当院で実施した小児の機能的単心室症に対する自己心臓内幹細胞移植の際に我々が行っている冠動脈バルーン閉鎖下心筋幹細胞注入の小児におけるまとまった報告は少ない.方法:岡山大学病院において冠動脈バルーン閉鎖下心筋幹細胞注入による自己心臓内幹細胞移植が第1相試験として2011年1月から2012年12月までに左心低形成症候群患者を対象に7例,また第2相試験として2013年7月から2015年3月までに機能的単心室症患者を対象に34例,合計41例に行われた.小児に対する冠動脈バルーン閉鎖下心筋幹細胞注入の手技,有害事象に関して検討を行った.結果:対象41例の自己心臓内幹細胞移植時の年齢と体重はそれぞれ中央値33ヵ月,10.1kgであった.冠動脈バルーン閉鎖下心筋幹細胞注入時に心電図上ST変化,血圧低下,脈拍低下,冠動脈攣縮を認めたが,いずれも一過性であり,重篤な合併症を認めず,全例で安全に手技を完遂できた.結語:冠動脈バルーン閉鎖下心筋幹細胞注入は機能的単心室症を有する小児においても安全に施行可能である.(著者抄録)

Dissecting the Left Heart Hypoplasia by Pluripotent Stem Cells

Junko Kobayashi, Shunji Sano, Hidemasa Oh

337 - 339 2016年

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

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

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

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

Current Management of Severe CHF by Mechanical Support and Cardiac Transplant 左心低形成症候群に対する心筋幹細胞を用いた再生医療

佐野俊二, 樽井俊, 石神修大, 小林純子, 後藤拓弥, 奥山倫弘, 逢坂大樹, 黒子洋介, 馬場健児, 大月審一, 新井禎彦, 笠原真悟, 王英正

日本小児循環器学会雑誌 31 ( Suppl.1 ) s1 - 147 2015年7月

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

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。

小児心不全に対する心臓内自己幹細胞移植療法による右室リモデリング退縮効果の解明

石神修大, 後藤拓弥, 奥山倫弘, 逢坂大樹, 新井禎彦, 笠原真悟, 佐野俊二, 王英正

日本外科学会定期学術集会抄録集 115回 CR - 2 2015年4月

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Stem cell engineering for cardiac tissue regeneration. 国際誌

Masashi Yoshida, Hidemasa Oh

Cardiology 115 ( 3 ) 191 - 3 2010年

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

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

心臓再生医療の現状と将来

竹原有史, 天野克也, 高橋知三郎, 王英正, 松原弘明

日本内科学会雑誌 98 ( 2 ) 343 - 350 2009年2月

記述言語：日本語出版者・発行元：The Japanese Society of Internal Medicine

循環器領域における再生医療とは血管新生とともに，最終的には心筋再生が目標である．梗塞の大きな急性心筋梗塞，再発性心不全を繰り返す難治性心不全患者が対象となる心臓再生医療には，現在まで様々なアプローチがなされてきたが，真に有効な治療法は見いだせていない．サイトカインを中心とした非細胞療法の使用法，適応決定や，骨髄細胞・骨格筋芽細胞から新たな可能性を求めて心筋幹細胞やiPS細胞等の開発も急務である．<br>

DOI： 10.2169/naika.98.343

その他リンク： https://jlc.jst.go.jp/DN/JALC/00326486151?from=CiNii

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

[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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

　前のページ - 次のページ　

1