MISC - 王　英正

Long-Term Clinical Outcome After Transcoronary Cardiosphere-DerivedCell Infusion in Patients With Single Ventricle Congenital Heart Disease. 査読

平井健太, 王 英正

Circulation   2023年11月

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Eight-year follow-up of cardiosphere-derived cell transplantation in patients with single ventricle congenital heart disease. 査読

平井健太, 王 英正

European Society of Cardiology   2023年9月

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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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担当区分：最終著者  

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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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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  

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

PubMed

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Exosomes Mediate Myocardial Regeneration of Cardiac Progenitor Cells in a Swine Model of Dilated Cardiomyopathy. 査読

平井健太, 王 英正

European Society of Cardiology.   2019年8月

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ラットを用いた心臓内幹細胞の高濃度静脈内投与における急性期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

日本再生医療学会総会(Web)   18th   2019年

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子ブタにおける新規フォンタン失敗モデルの生存を改善するための下大静脈バンディングの影響

王英正, 後藤拓弥, 逢坂大樹, 平井健太

日本循環器学会学術集会(Web)   83rd   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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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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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

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記述言語：英語  

DOI： 10.1161/CIRCRESAHA.117.312311.

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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

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

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: +8.410.0% versus +1.66.4%, 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.

DOI： 10.1161/CIRCRESAHA.117.312311.

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大動物フォンタン循環類似モデルと下大静脈絞扼によるプレコンディショニング戦略の検討

後藤拓弥, 逢坂大樹, 平井健太, 佐野俊和, 王英正

日本再生医療学会総会(Web)   17th   2018年

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大動物フォンタン術後遠隔期モデルを目指した下大静脈絞扼術による臓器障害評価

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の効果検証~大型動物実験からヒト第1相臨床試験へ~

平井健太, 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, 原真祐子, 後藤拓弥, 逢坂大樹, 王英正

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

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大動物フォンタン循環モデル作成に向けた下大静脈絞扼によるプレコンディショニング戦略の検証

逢坂大樹, 後藤拓弥, 佐野俊和, 平井健太, 笠原真悟, 王英正

日本循環器学会学術集会(Web)   82nd   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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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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Effects and Clinical Outcomes of Cardiac Progenitor Cell Infusion at Two Years in the Single Ventricle Cell Therapy Trials

Toshikazu Sano, Shuta Ishigami, Daiki Ousaka, Kenta Hirai, Takuya Goto, Shunji Sano, Hidemasa Oh

CIRCULATION   136   2017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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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

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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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DOI： 10.1111/ped.13485.

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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

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DOI： 10.1161/CIRCRESAHA.117.309697.

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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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DOI： 10.1111/ped.13485.

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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

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DOI： 10.1161/CIRCRESAHA.117.309697.

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新規ブタ単心室モデルを用いた先天性心疾患に対する新たな細胞治療法の開発

後藤拓弥, 逢坂大樹, 平井健太, 佐野俊和, 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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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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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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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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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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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, 大月審一, 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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小児単心室症に対する心筋再生医療における治療反応予測因子の検討と5年間に及ぶ長期追跡調査報告

石神修大, 後藤拓弥, 逢坂大樹, 大月審一, 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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小児単心室症に対する心筋再生医療における治療反応予測因子の検討と5年間に及ぶ長期追跡調査報告

石神修大, 後藤拓弥, 逢坂大樹, 大月審一, 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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左心低形成症候群に対する心臓内幹細胞自家移植療法(TICAP第1相臨床試験)の3年目長期成績

石神修大, 樽井俊, 後藤拓弥, 逢坂大樹, 大月審一, 笠原真悟, 佐野俊二, 王英正

再生医療   15   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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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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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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DOI： 10.14800/sce.550

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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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DOI： 10.14800/scti.800

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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

後藤 拓弥, 石神 修大, 逢坂 大樹, 佐野 俊二, 王 英正

日本小児血液・がん学会誌   52 ( 3 )   210 - 219   2015年

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記述言語：日本語   出版者・発行元：日本小児血液・がん学会  

近年，再生医療の研究はますます盛んになり，心不全に対する心筋再生医療の臨床治験が徐々に報告されるようになった．初期技術として，骨髄幹細胞や間葉系幹細胞，臍帯血幹細胞などを用いた研究ではその有用性を示す報告が相次いでいる．とりわけ2002年の心筋幹細胞の発見は，心筋再生医療に大きな希望をもたらした．心筋幹細胞は他の幹細胞に比べ，より高い治療効果が期待されており，成人虚血性心疾患に対する心筋幹細胞移植は，海外での臨床治験が報告されており，治療効果が示されている．一方，先天性心疾患の一部の重症疾患群では，救命不能な症例がいまだ存在する．今回我々は，世界初の小児心疾患に対する心筋幹細胞移植療法の第1相臨床研究（TICAP試験）を行い，心臓内幹細胞移植療法の安全性と治療効果を確認した．続いて，第2相臨床研究（PERSEUS試験）を現在施行中であり，心筋幹細胞治療の標準医療化を目指している．一方，これまでの多くの臨床試験の初期成績により，心臓幹細胞移植療法の治療効果は確認されつつあるが，その作用機序は，幹細胞の心筋細胞への分化に加え，幹細胞の分泌するある種のサイトカインの関与などが考えられている．また，心臓への幹細胞の生着性を上げることでより高い治療効果を得られる可能性があり，心臓への移植細胞の誘導や足場となる生体材料の併用など様々な試みがなされている．近いうちに，心臓再生医療が心疾患の新しい治療手段となる時代が到来するであろう．

DOI： 10.11412/jspho.52.210

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その他リンク： http://search.jamas.or.jp/link/ui/2016089029

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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DOI： 10.9794/jspccs.31.138

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心臓超音波検査による心臓内幹細胞自家移植療法に伴う心筋ストレイン変化の機能解析

逢坂大樹, 石神修大, 奥山倫弘, 後藤拓哉, 大月審一, 佐野俊二, 王英正

日本心エコー図学会学術集会抄録集   26th   2015年

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心臓超音波および心臓MRIを用いた心臓内幹細胞自家移植療法に伴う心筋ストレイン変化の解析

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

日本小児循環器学会雑誌   31 ( Supplement 1 )   2015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I相臨床試験(TICAP trial)の3年長期成績報告

石神修大, 樽井俊, 大月審一, 後藤拓弥, 奥山倫弘, 逢坂大樹, 栄徳隆祐, 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   31 ( Supplement 1 )   2015年

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単心室症におけるHeart Failure with Preserved Ejection Fractionに対する心臓シャント手術及び心臓内幹細胞自家移植療法の効果

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

日本小児循環器学会雑誌   31 ( Supplement 1 )   2015年

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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 ( Supplement 1 )   2015年

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繊維化心筋を有する小児単心室症の心臓MRIによる機能解析と心筋幹細胞移植療法による繊維化抑制の可能性

石神修大, 後藤拓弥, 逢坂大樹, 奥山倫弘, 栄徳隆裕, 馬場健児, 大月審一, 笠原真悟, 佐野俊二, 王英正

日本小児循環器学会雑誌   31 ( Supplement 1 )   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へ向けた取り組み

石神修大, 後藤拓弥, 奥山倫弘, 逢坂大樹, 新井禎彦, 笠原真悟, 大月審一, 佐野俊二, 王英正

日本小児循環器学会雑誌   31 ( Supplement 1 )   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

後藤拓弥, 石神修大, 逢坂大樹, 佐野俊二, 王英正

日本小児血液・がん学会雑誌(Web)   52 ( 3 )   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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Late Gadolinium Enhancement on Cardiac MRI Identifies Ventricular Dysfunction and Regional Myocardial Dyssynchrony in Patients with Univentricular Heart Diseases

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

CIRCULATION RESEARCH   115   2014年7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 Children With Hypoplastic Left Heart Syndrome: 2-year Results Of The Ticap Trial

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

CIRCULATION RESEARCH   115   2014年7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/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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記述言語：英語  

DOI： 10.1073/pnas.1315359111

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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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3D細胞外マトリックスを利用したヒト幹細胞再播種によるバイオ人工心臓の作成

奥山倫弘, 逢坂大樹, 石神修大, 小林純子, 笠原真悟, 新井禎彦, 佐野俊二, 王英正

再生医療   13   2014年

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機能的単心室症に対する心臓内幹細胞自家移植療法:第I/II相臨床試験の2年目長期成績

石神修大, 樽井俊, 奥山倫弘, 逢坂大機, 大月審一, 栄徳隆祐, 小林純子, 笠原真悟, 佐野俊二, 王英正

日本小児循環器学会雑誌   30 ( Supplement )   2014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1相試験(TICAP)

樽井俊, 石神修大, 大月審一, 逢坂大樹, 栄徳隆裕, 近藤麻衣子, 小林純子, 奥山倫弘, 馬場健児, 川畑拓也, 吉積功, 黒子洋介, 新井禎彦, 岩崎達雄, 佐藤修平, 笠原真悟, 佐野俊二, 王英正

再生医療   13   2014年

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心臓MRIの遅延造影を用いた幼児期単心室症患者における心筋線維化の検出と臨床的意義

逢坂大樹, 石神修大, 奥山倫弘, 小林純子, 樽井俊, 笠原真悟, 佐野俊二, 王英正

日本小児循環器学会雑誌   30 ( Supplement )   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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ハーフクリップ法によるラット右心負荷モデルの作製

奥山倫弘, 平田昌敬, 逢坂大樹, 樽井俊, 小林純子, 笠原真悟, 佐野俊二, 王英正

日本心臓血管外科学会雑誌   42 ( Supplement )   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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Hedgehog Interacting Protein Controls Age-Dependent Angiogenic Activity in Human Cardiac Progenitor Cells Through Insulin-Like Growth Factor-1 Receptor Signaling

Masashi Yoshida, Suguru Tarui, Junko Kobayashi, Masataka Hirata, Yasufumi Kijima, Tohru Miyoshi, Kazufumi Nakamura, Kengo Kusano, Youhei Maeshima, Shunji Sano, Hiroshi Ito, 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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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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MURC, Muscle-Restricted Coiled-Coil Protein, Regulates Caveolae Morphology and Induces Hypertrophy in Cardiomyocytes

Takuya Taniguchi, Takehiro Ogata, Daisuke Naito, Naohiko Nakanishi, Kotaro Miyagawa, Katsuya Amano, Koji Isodono, Hiroko Imoto, Masashi Tagawa, Naofumi Takehara, Satoshi Asada, Atsuo Adachi, Tatsuya Morimoto, Tomosaburo Takahashi, Hidemasa Oh, Tomomi Ueyama, Hiroaki Matsubara

CIRCULATION   122 ( 21 )   2010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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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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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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記述言語：日本語  

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3 Human cardiac stem cell biotherapy Integrated with bFGF controlled-release : Two randomized, dose-ranging, controlled preclinical trial(Symposium 12 (SY-12) (M) Clinical Experiences of Regenerative Medicine in Cardiovascular Diseases,Special Program,The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

Takehara Naofumi, Tabata Yasuhiko, Tsutsumi Yoshiaki, Matsubara Hiroaki, Oh Hidemasa

Circulation journal : official journal of the Japanese Circulation Society   72   48 - 48   2008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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OE-237 Dose-dependent Functional Recovery of Human Cardiac Stem Cell Transplantation Combined with Control-Delivery of Angiogenic Growth Factor in Chronic Myocardial Infarction(Regeneration(angiogenesis/myocardial regeneration)(01)(M),Oral Presentation(English),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

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

Circulation journal : official journal of the Japanese Circulation Society   72   240 - 240   2008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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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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生体組織工学的手法を用いた心筋幹細胞とその特異的増幅因子を導入するハイブリッド移植療法の開発

王英正, 小形岳寛, 野村哲矢, 浅田聡, 上山知己

医科学応用研究財団研究報告   25   173 - 177   2008年

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記述言語：日本語   出版者・発行元：(公財)鈴木謙三記念医科学応用研究財団  

心筋幹細胞Myosphere-derived progenitor cells(MDPCs)をSAGE法を用いて遺伝子発現の解析を行い、SST法を用いてMDPCsより分泌される蛋白の同定を行った。その結果、osteopontin(OPN)が未分化MDPCsの増殖に最も重要である因子である可能性が考えられた。同定したOPNの発現を骨格筋組織由来の細胞およびMDPCsを用いて染色し、その発現量は幹細胞に富むMDPCsにおいて有意に亢進していることが明らかとなった。また、OPN刺激によりMDPCsの細胞数も増加していた。このことから、OPNのMDPCsの増殖にに対する作用が明らかとなった。さらに、OPNの増殖に及ぼす細胞内情報伝達経路の検討を行ったところ、OPN刺激によりAkt/GSK3βが活性化させることが明らかとなった。以上の結果から、phosphoinositide 3-kinaseを介したAkt活性化がOPNによるMDPCsの増殖に重要であると推測された。

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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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心臓幹細胞移植による心筋再生医療の臨床応用への可能性 (特集 心筋再生と心筋保護)

王 英正

呼吸と循環   55 ( 7 )   721 - 726   2007年7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/2007274856

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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記述言語：日本語  

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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

心筋前駆細胞の発見による重症心不全への新たな細胞移植療法の到来

王 英正

臨床病理 = THE OFFICIAL JOURNAL OF JAPANESE SOCIETY OF LABORATORY MEDICINE   52   44 - 44   2004年7月

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記述言語：日本語  

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