研究者詳細 - 王　英正

論文 - 王　英正

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

Hidemasa Oh

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

記述言語：日本語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

Hidemasa Oh, Michael D Schneider

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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