Bone Marrow Cells Can Be Converted Into Cardiac Competent Progenitors Via Inhibition Of G9a Histone Methyltransferase G9a

Given that the optimal treatment for the damaged heart is to replace dysfunctional myocytes, great effort has been made to develop stem cell therapies for regenerating cardiomyocytes (CM). We demonstrated previously that bone marrow (BM) have a capacity, albeit limited, to convert into CM. To improve the yields of CM from BM, we screened various molecules that were reported to assist the induction of induced pluripotent stem cells (iPSC) from somatic cells, for their effect in enhancing BM cardiopotency. From this experimentation, we identified BIX01294, a selective inhibitor of G9a histone methyltransferase (HMTase), as a candidate for reprograming BM cells to a cardiopotent phenotype, as indicated by the upregulation of precardiac genes (Brachyury, Mesp‐1 and Isl‐1). Knockdown of G9a HMTase by shRNA provided supporting evidence that inhibiting this enzyme promotes the conversion of BM cells to cardiopotent progenitors. Moreover, in response to the cardiac inducer Wnt11, BM cells pretreated with BIX01294 had much more profound expression of myocardial genes and proteins, including Nkx2.5, Gata4, Hand1, Hand2, Tbx5, myocardin, α‐actinin, and titin. In summary, these data indicate that promoting specific epigenetic modification by pharmacological inhibitor BIX01294 can assist the conversion of BM cells into cardiopotent progenitor cells that may have utility for in vivo cardiac repair and regeneration. Grant Funding Source : NIH NHLBI HL086815