Adult Cardiac Myogenesis by Heart-derived Progenitor Cells

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The creation of new cardiac myocytes in adults, by the specification of adult progenitor cells, is reported both as an intrinsic mechanism of cardiac repair and as an opportunity for therapeutic intervention, by the activation of endogenous marrow-derived progenitor cells. During the previous cycle of PPG support, our investigations of inductive signals for cardiac development led us to discover a novel, adult, heart-derived progenitor cell with the following properties: (1) No cardiac structural genes are expressed. (2) Many cardiogenic transcription factors are expressed (GATA-4, TEF-1, Tbx5, low levels of MEF2C), although not Nkx2.5. (3) No expression of ALK3, the type IA receptor for bone morphogenetic proteins (Bmpr1a). (4) Homing to infarcted myocardium when given intravenously, followed by differentiation in situ. (5) Differentiation includes both fusion-independent and fusion-associated components, proven with a Cre/Iox donor/recipient system. (6) The cells differentiate in culture after 5'-azacytidine, concurrent with induction of Bmpr1a. (7) Cre-mediated excision of Bmpr1a prevents up-regulation of MEF2c and the induction of alphaMHC. Based on these findings, we propose to study fundamental mechanisms for adult cardiac myogenesis by this novel, heart-derived cardiac progenitor cell population: 1. To establish, more thoroughly, the phenotype of adult cardiac progenitor cells, by a candidate gene approach, expression profiling, studies of sub-populations retrieved by fluorescence and magnetic sorting, and clonal isolation. 2. To identify the responsible signaling pathway for Bmpr1a-dependent differentiation of adult cardiac progenitor cells, using dominant-inhibitors, interference with expression, and conditional alleles for Smads and TAK1, the candidate effectors. 3. To investigate the Bmpr1a-independent differentiation of adult cardiac progenitor cells, with emphasis on the signaling and transcriptional mechanisms for induction of Nkx2.5. 4. To test the hypothesis that adult cardiac progenitor cells are predisposed to convert to the cardiac phenotype, as a consequence of the transcription factors expressed even at baseline, by gain- and loss-of-function studies.