Abstract
BackgroundMyocardial infarction (MI) due to coronary artery disease remains one of the leading causes of premature death. Replacement of infarcted heart tissue with regenerating myocardium from endogenous progenitor pools or exogenously introduced stem cells remains a therapeutic ideal. Their impracticality mainly lies in their low efficiency in cardiogenic differentiation (CD). Our recent studies with an acute MI animal model have already demonstrated the therapeutic effect of the MeOH extract of Geum japonicum (EGJ), providing clear evidence of myocardial regeneration.Methods and FindingsThe present study further isolated the active component contained in EGJ using bioassay-guided isolation and investigated its efficacy in the treatment of infarcted heart in animal MI models. We demonstrated that substantial repair of infarcted heart in animal MI models by EGJ can be mimicked by the isolated candidate compound (cardiogenin) in MI animal models. Clear evidence of newly regenerated endogenous mesenchymal stem cells (MSCs) derived cardiomyocytes was observed throughout the infarct zone, accompanied by significantly improved functional performance of the heart. Transplantation of MSCs pretreated with EGJ or cardiogenin into a MI animal model also resulted in substantial regeneration of functional myocardium, implying that the activated MSCs carry all the necessary blueprints for myocardial regeneration. Signaling pathways specific to cell survival, CD identified in embryonic heart induction and angiogenesis were activated in both cardiogenin-treated MSCs and cardiogenin-induced regenerating myocardium.ConclusionsThis study has demonstrated the therapeutic effects of cardiogenin in infarcted heart repair, and identified the associated signalling pathways for effective cardiogenic differentiation of MSCs, cell survival and angiogenesis. These findings should enable new treatment strategies for MI to be developed immediately.
Highlights
Despite significant therapeutic advances, replacement of infarcted heart tissue with regenerating myocardium remains a therapeutic ideal as it is almost impossible for adult cardiomyocytes to repopulate [1,2,3,4,5,6,7,8]
This study has demonstrated the therapeutic effects of cardiogenin in infarcted heart repair, and identified the associated signalling pathways for effective cardiogenic differentiation of mesenchymal stem cells (MSCs), cell survival and angiogenesis
Considerable efforts have been focused on searching for new ways to enhance cardiogenic differentiation efficiency (CDE) from a variety of potential progenitor cells, including embryonic stem cells, hemotopoietic stem cells and MSCs, since this is essential for myocardial regeneration as a viable and practical therapy for Myocardial infarction (MI)
Summary
Replacement of infarcted heart tissue with regenerating myocardium remains a therapeutic ideal as it is almost impossible for adult cardiomyocytes to repopulate [1,2,3,4,5,6,7,8]. Transplantation of adult bone marrow (BM) derived MSCs following MI has been shown to produce some cardiomyogenesis, but majority of the newly regenerated cardiomyocytes appeared to be scattered along the less-ischemic border zone [7,8]. This signifies that the transplanted MSCs had insufficient CD to form the integrated units necessary for regenerating functional myocardium. Replacement of infarcted heart tissue with regenerating myocardium from endogenous progenitor pools or exogenously introduced stem cells remains a therapeutic ideal. Their impracticality mainly lies in their low efficiency in cardiogenic differentiation (CD). Our recent studies with an acute MI animal model have already demonstrated the therapeutic effect of the MeOH extract of Geum japonicum (EGJ), providing clear evidence of myocardial regeneration
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