The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mark T Keating - One of the best experts on this subject based on the ideXlab platform.
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periostin induces proliferation of differentiated Cardiomyocytes and promotes cardiac repair
Nature Medicine, 2007Co-Authors: Bernhard Kuhn, Mark T Keating, Federica Del Monte, Roger J Hajjar, Yuhshin Chang, Djamel Lebeche, Shima ArabAbstract:Adult mammalian hearts respond to injury with scar formation and not with cardiomyocyte proliferation, the cellular basis of regeneration. Although cardiogenic progenitor cells may maintain myocardial turnover, they do not give rise to a robust regenerative response. Here we show that extracellular periostin induced reentry of differentiated mammalian Cardiomyocytes into the cell cycle. Periostin stimulated mononucleated Cardiomyocytes to go through the full mitotic cell cycle. Periostin activated alphaV, beta1, beta3 and beta5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin-induced reentry of Cardiomyocytes into the cell cycle and was sufficient for cell-cycle reentry in the absence of periostin. After myocardial infarction, periostin-induced cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced fibrosis and infarct size, and increased angiogenesis. Thus, periostin and the pathway that it regulates may provide a target for innovative strategies to treat heart failure.
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fgf1 p38 map kinase inhibitor therapy induces cardiomyocyte mitosis reduces scarring and rescues function after myocardial infarction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Feli Engel, Patrick C H Hsieh, Richard T Lee, Mark T KeatingAbstract:Mammalian Cardiomyocytes have limited proliferation potential, and acutely injured mammalian hearts do not regenerate adequately. Instead, injured myocardium develops fibrosis and scarring. Here we show that FGF1/p38 MAP kinase inhibitor treatment after acute myocardial injury in 8- to 10-week-old rats increases cardiomyocyte mitosis. At 3 months after injury, 4 weeks of FGF1/p38 MAP kinase inhibitor therapy results in reduced scarring and wall thinning, with markedly improved cardiac function. In contrast, p38 MAP kinase inhibition alone fails to rescue heart function despite increased cardiomyocyte mitosis. FGF1 improves angiogenesis, possibly contributing to the survival of newly generated Cardiomyocytes. Our data indicate that FGF1 and p38 MAP kinase, proteins involved in cardiomyocyte proliferation and angiogenesis during development, may be delivered therapeutically to enhance cardiac regeneration.
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p38 map kinase inhibition enables proliferation of adult mammalian Cardiomyocytes
Genes & Development, 2005Co-Authors: Felix B Engel, Michael Schebesta, Mychelle T Duong, Shuxun Ren, Jeffery B Madwed, Huiping Jiang, Yibin Wang, Mark T KeatingAbstract:Adult mammalian Cardiomyocytes are considered terminally differentiated and incapable of proliferation. Consequently, acutely injured mammalian hearts do not regenerate, they scar. Here, we show that adult mammalian Cardiomyocytes can divide. One important mechanism used by mammalian Cardiomyocytes to control cell cycle is p38 MAP kinase activity. p38 regulates expression of genes required for mitosis in Cardiomyocytes, including cyclin A and cyclin B. p38 activity is inversely correlated with cardiac growth during development, and its overexpression blocks fetal cardiomyocyte proliferation. Activation of p38 in vivo by MKK3bE reduces BrdU incorporation in fetal Cardiomyocytes by 17.6%. In contrast, cardiac-specific p38α knockout mice show a 92.3% increase in neonatal cardiomyocyte mitoses. Furthermore, inhibition of p38 in adult Cardiomyocytes promotes cytokinesis. Finally, mitosis in adult Cardiomyocytes is associated with transient dedifferentiation of the contractile apparatus. Our findings establish p38 as a key negative regulator of cardiomyocyte proliferation and indicate that adult Cardiomyocytes can divide.
Chunxiang Zhang - One of the best experts on this subject based on the ideXlab platform.
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Knockdown of the HDAC1 promotes the directed differentiation of bone mesenchymal stem cells into Cardiomyocytes.
PLOS ONE, 2014Co-Authors: Dong-feng Lu, Ying Wang, Zi-zhuo Su, Zhao-hua Zeng, Xiao-wen Xing, Zhi-yu He, Chunxiang ZhangAbstract:Failure of the directed differentiation of the transplanted stem cells into Cardiomyocytes is still a major challenge of cardiac regeneration therapy. Our recent study has demonstrated that the expression of histone deacetylase 1 (HDAC1) is decreased in bone mesenchymal stem cells (BMSCs) during their differentiation into Cardiomyocytes. However, the potential roles of HDAC1 in cardiac cell differentiation of BMSCs, as well as the mechanisms involved are still unclear. In current study, the expression of HDAC1 in cultured rat BMSCs is knocked down by lentiviral vectors expressing HDAC1-RNAi. The directed differentiation of BMSCs into Cardiomyocytes is evaluated by the expression levels of cardiomyocyte-related genes such as GATA-binding protein 4 (GATA-4), Nirenberg, Kim gene 2 homeobox 5 (Nkx2.5), cardiac troponin T (CTnT), myosin heavy chain (MHC), and connexin-43. Compared with that in control BMSCs, the expression of these cardiomyocyte-related genes is significantly increased in these HDAC1 deficient stem cells. The results suggest that HDAC1 is involved in the cardiomyocyte differentiation of BMSCs. Knockdown of the HDAC1 may promote the directed differentiation of BMSCs into Cardiomyocytes.
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Knockdown of the HDAC1 Promotes the Directed Differentiation of Bone Mesenchymal Stem Cells into
2014Co-Authors: Chunxiang ZhangAbstract:Failure of the directed differentiation of the transplanted stem cells into Cardiomyocytes is still a major challenge of cardiac regeneration therapy. Our recent study has demonstrated that the expression of histone deacetylase 1 (HDAC1) is decreased in bone mesenchymal stem cells (BMSCs) during their differentiation into Cardiomyocytes. However, the potential roles of HDAC1 in cardiac cell differentiation of BMSCs, as well as the mechanisms involved are still unclear. In current study, the expression of HDAC1 in cultured rat BMSCs is knocked down by lentiviral vectors expressing HDAC1-RNAi. The directed differentiation of BMSCs into Cardiomyocytes is evaluated by the expression levels of cardiomyocyte-related genes such as GATA-binding protein 4 (GATA-4), Nirenberg, Kim gene 2 homeobox 5 (Nkx2.5), cardiac troponin T (CTnT), myosin heavy chain (MHC), and connexin-43. Compared with that in control BMSCs, the expression of these cardiomyocyte-related genes is significantly increased in these HDAC1 deficient stem cells. The results suggest that HDAC1 is involved in the cardiomyocyte differentiation of BMSCs. Knockdown of the HDAC1 may promote the directed differentiation of BMSCs into Cardiomyocytes
Charles E. Murry - One of the best experts on this subject based on the ideXlab platform.
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quantitative proteomics identify dab2 as a cardiac developmental regulator that inhibits wnt β catenin signaling
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Peter Hofsteen, Aaron M Robitaille, Daniel Patrick Chapman, Randall T Moon, Charles E. MurryAbstract:To reveal the molecular mechanisms involved in cardiac lineage determination and differentiation, we quantified the proteome of human embryonic stem cells (hESCs), cardiac progenitor cells (CPCs), and Cardiomyocytes during a time course of directed differentiation by label-free quantitative proteomics. This approach correctly identified known stage-specific markers of cardiomyocyte differentiation, including SRY-box2 (SOX2), GATA binding protein 4 (GATA4), and myosin heavy chain 6 (MYH6). This led us to determine whether our proteomic screen could reveal previously unidentified mediators of heart development. We identified Disabled 2 (DAB2) as one of the most dynamically expressed proteins in hESCs, CPCs, and Cardiomyocytes. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mutagenesis in zebrafish to assess whether DAB2 plays a functional role during cardiomyocyte differentiation. We found that deletion of Dab2 in zebrafish embryos led to a significant reduction in cardiomyocyte number and increased endogenous WNT/β-catenin signaling. Furthermore, the Dab2-deficient defects in cardiomyocyte number could be suppressed by overexpression of dickkopf 1 (DKK1), an inhibitor of WNT/β-catenin signaling. Thus, inhibition of WNT/β-catenin signaling by DAB2 is essential for establishing the correct number of Cardiomyocytes in the developing heart. Our work demonstrates that quantifying the proteome of human stem cells can identify previously unknown developmental regulators.
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survival integration and differentiation of cardiomyocyte grafts a study in normal and injured rat hearts
Circulation, 1999Co-Authors: Hans Reinecke, Ming Zhang, Trudy Bartosek, Charles E. MurryAbstract:Background—Cardiomyocyte grafting augments myocyte numbers in the heart. We investigated (1) how developmental stage influences graft survival; (2) whether acutely necrotic or healing cardiac lesions support grafts; and (3) the differentiation and integration of cardiomyocyte grafts in injured hearts. Methods and Results—Cardiomyocytes from fetal, neonatal, or adult inbred rats were grafted into normal myocardium, acutely cryoinjured myocardium, or granulation tissue (6 days after injury). Adult Cardiomyocytes did not survive under any conditions. In contrast, fetal and neonatal Cardiomyocytes formed viable grafts under all conditions. Time-course studies with neonatal Cardiomyocytes showed that the grafts recapitulated many aspects of normal development. The adherens junction protein N-cadherin was distributed circumferentially at day 1 but began to organize into intercalated disk–like structures by day 6. The gap junction protein connexin43 followed a similar but delayed pattern relative to N-cadherin. ...
Bin Zhou - One of the best experts on this subject based on the ideXlab platform.
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rest regulates the cell cycle for cardiac development and regeneration
Nature Communications, 2017Co-Authors: Donghong Zhang, Yidong Wang, Ping Wang, Xinchun Yuan, Jianyun Yan, Chenleng Cai, Ching Pin Chang, Deyou Zheng, Bin ZhouAbstract:Despite the importance of cardiomyocyte proliferation in cardiac development and regeneration, the mechanisms that promote cardiomyocyte cell cycle remain incompletely understood. RE1 silencing transcription factor (REST) is a transcriptional repressor of neuronal genes. Here we show that REST also regulates the cardiomyocyte cell cycle. REST binds and represses the cell cycle inhibitor gene p21 and is required for mouse cardiac development and regeneration. Rest deletion de-represses p21 and inhibits the cardiomyocyte cell cycle and proliferation in embryonic or regenerating hearts. By contrast, REST overexpression in cultured Cardiomyocytes represses p21 and increases proliferation. We further show that p21 knockout rescues cardiomyocyte cell cycle and proliferation defects resulting from Rest deletion. Our study reveals a REST-p21 regulatory axis as a mechanism for cell cycle progression in Cardiomyocytes, which might be exploited therapeutically to enhance cardiac regeneration.
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dedifferentiation proliferation and redifferentiation of adult mammalian Cardiomyocytes after ischemic injury
Circulation, 2017Co-Authors: Wei Eric Wang, Xuewei Xia, Qiao Liao, Cong Lan, Dezhong Yang, Hongmei Chen, Rongchuan Yue, C Zeng, Lin Zhou, Bin ZhouAbstract:Background: Adult mammalian hearts have a limited ability to generate new Cardiomyocytes. Proliferation of existing adult Cardiomyocytes (ACMs) is a potential source of new Cardiomyocytes. Understanding the fundamental biology of ACM proliferation could be of great clinical significance for treating myocardial infarction (MI). We aim to understand the process and regulation of ACM proliferation and its role in new cardiomyocyte formation of post-MI mouse hearts. Methods: β-Actin-green fluorescent protein transgenic mice and fate-mapping Myh6-MerCreMer-tdTomato/lacZ mice were used to trace the fate of ACMs. In a coculture system with neonatal rat ventricular myocytes, ACM proliferation was documented with clear evidence of cytokinesis observed with time-lapse imaging. Cardiomyocyte proliferation in the adult mouse post-MI heart was detected by cell cycle markers and 5-ethynyl-2-deoxyuridine incorporation analysis. Echocardiography was used to measure cardiac function, and histology was performed to determine infarction size. Results: In vitro, mononucleated and bi/multinucleated ACMs were able to proliferate at a similar rate (7.0%) in the coculture. Dedifferentiation proceeded ACM proliferation, which was followed by redifferentiation. Redifferentiation was essential to endow the daughter cells with cardiomyocyte contractile function. Intercellular propagation of Ca 2+ from contracting neonatal rat ventricular myocytes into ACM daughter cells was required to activate the Ca 2+ -dependent calcineurin-nuclear factor of activated T-cell signaling pathway to induce ACM redifferentiation. The properties of neonatal rat ventricular myocyte Ca 2+ transients influenced the rate of ACM redifferentiation. Hypoxia impaired the function of gap junctions by dephosphorylating its component protein connexin 43, the major mediator of intercellular Ca 2+ propagation between Cardiomyocytes, thereby impairing ACM redifferentiation. In vivo, ACM proliferation was found primarily in the MI border zone. An ischemia-resistant connexin 43 mutant enhanced the redifferentiation of ACM-derived new Cardiomyocytes after MI and improved cardiac function. Conclusions: Mature ACMs can reenter the cell cycle and form new Cardiomyocytes through a 3-step process: dedifferentiation, proliferation, and redifferentiation. Intercellular Ca 2+ signal from neighboring functioning Cardiomyocytes through gap junctions induces the redifferentiation process. This novel mechanism contributes to new cardiomyocyte formation in post-MI hearts in mammals.
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yap1 the nuclear target of hippo signaling stimulates heart growth through cardiomyocyte proliferation but not hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Alexander Von Gise, Karin Schlegelmilch, Leah B Honor, Jessica N Buck, Takahiro Ishiwata, Bin Zhou, Fernando D Camargo, William T PuAbstract:Heart growth is tightly controlled so that the heart reaches a predetermined size. Fetal heart growth occurs through cardiomyocyte proliferation, whereas postnatal heart growth involves primarily physiological cardiomyocyte hypertrophy. The Hippo kinase cascade is an important regulator of organ growth. A major target of this kinase cascade is YAP1, a transcriptional coactivator that is inactivated by Hippo kinase activity. Here, we used both genetic gain and loss of Yap1 function to investigate its role in regulating proliferative and physiologic hypertrophic heart growth. Fetal Yap1 inactivation caused marked, lethal myocardial hypoplasia and decreased cardiomyocyte proliferation, whereas fetal activation of YAP1 stimulated cardiomyocyte proliferation. Enhanced proliferation was particularly dramatic in trabecular Cardiomyocytes that normally exit from the cell cycle. Remarkably, YAP1 activation was sufficient to stimulate proliferation of postnatal Cardiomyocytes, both in culture and in the intact heart. A dominant negative peptide that blocked YAP1 binding to TEAD transcription factors inhibited YAP1 proliferative activity, indicating that this activity requires YAP1–TEAD interaction. Although Yap1 was a critical regulator of cardiomyocyte proliferation, it did not influence physiological hypertrophic growth of Cardiomyocytes, because postnatal Yap1 gain or loss of function did not significantly alter cardiomyocyte size. These studies demonstrate that Yap1 is a crucial regulator of cardiomyocyte proliferation, cardiac morphogenesis, and myocardial trabeculation. Activation of Yap1 in postnatal Cardiomyocytes may be a useful strategy to stimulate cardiomyocyte expansion in therapeutic myocardial regeneration.
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yap1 the nuclear target of hippo signaling stimulates heart growth through cardiomyocyte proliferation but not hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Alexander Von Gise, Karin Schlegelmilch, Leah B Honor, Jessica N Buck, Takahiro Ishiwata, Bin Zhou, Zhiqiang Lin, Gina M Pan, Fernando D CamargoAbstract:Heart growth is tightly controlled so that the heart reaches a predetermined size. Fetal heart growth occurs through cardiomyocyte proliferation, whereas postnatal heart growth involves primarily physiological cardiomyocyte hypertrophy. The Hippo kinase cascade is an important regulator of organ growth. A major target of this kinase cascade is YAP1, a transcriptional coactivator that is inactivated by Hippo kinase activity. Here, we used both genetic gain and loss of Yap1 function to investigate its role in regulating proliferative and physiologic hypertrophic heart growth. Fetal Yap1 inactivation caused marked, lethal myocardial hypoplasia and decreased cardiomyocyte proliferation, whereas fetal activation of YAP1 stimulated cardiomyocyte proliferation. Enhanced proliferation was particularly dramatic in trabecular Cardiomyocytes that normally exit from the cell cycle. Remarkably, YAP1 activation was sufficient to stimulate proliferation of postnatal Cardiomyocytes, both in culture and in the intact heart. A dominant negative peptide that blocked YAP1 binding to TEAD transcription factors inhibited YAP1 proliferative activity, indicating that this activity requires YAP1–TEAD interaction. Although Yap1 was a critical regulator of cardiomyocyte proliferation, it did not influence physiological hypertrophic growth of Cardiomyocytes, because postnatal Yap1 gain or loss of function did not significantly alter cardiomyocyte size. These studies demonstrate that Yap1 is a crucial regulator of cardiomyocyte proliferation, cardiac morphogenesis, and myocardial trabeculation. Activation of Yap1 in postnatal Cardiomyocytes may be a useful strategy to stimulate cardiomyocyte expansion in therapeutic myocardial regeneration.
Michael A Laflamme - One of the best experts on this subject based on the ideXlab platform.
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human pluripotent stem cells prospects and challenges as a source of Cardiomyocytes for in vitro modeling and cell based cardiac repair
Advanced Drug Delivery Reviews, 2016Co-Authors: Matthew E Hartman, Michael A LaflammeAbstract:Human pluripotent stem cells (PSCs) represent an attractive source of Cardiomyocytes with potential applications including disease modeling, drug discovery and safety screening, and novel cell-based cardiac therapies. Insights from embryology have contributed to the development of efficient, reliable methods capable of generating large quantities of human PSC-Cardiomyocytes with cardiac purities ranging up to 90%. However, for human PSCs to meet their full potential, the field must identify methods to generate cardiomyocyte populations that are uniform in subtype (e.g. homogeneous ventricular Cardiomyocytes) and have more mature structural and functional properties. For in vivo applications, cardiomyocyte production must be highly scalable and clinical grade, and we will need to overcome challenges including graft cell death, immune rejection, arrhythmogenesis, and tumorigenic potential. Here we discuss the types of human PSCs, commonly used methods to guide their differentiation into Cardiomyocytes, the phenotype of the resultant Cardiomyocytes, and the remaining obstacles to their successful translation.
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Cardiomyocytes derived from human embryonic stem cells in pro survival factors enhance function of infarcted rat hearts
Nature Biotechnology, 2007Co-Authors: Michael A Laflamme, Hans Reinecke, Kent Chen, Anna V Naumova, Veronica Muskheli, James A Fugate, Sarah K Dupras, Mohammad Hassanipour, Chris Osullivan, Lila R CollinsAbstract:Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into Cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell-derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human Cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell-derived Cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.