Adult Cardiac Myogenesis by Heart-derived Progenitor Cells

据报道，通过成人祖细胞的规范，成人新心肌细胞的产生既是心脏修复的内在机制，也是通过内源性骨髓源性祖细胞的激活进行治疗干预的机会。在之前的PPG支持周期中，我们对心脏发育的诱导信号的研究使我们发现了一种新的成年心脏源性祖细胞，其具有以下特性：(1)不表达心脏结构基因。(2)许多心源性转录因子（GATA-4、TEF-1、Tbx5、低水平MEF2C）均有表达，但未表达Nkx2.5。(3)骨形态发生蛋白IA型受体ALK3 （Bmpr1a）未表达。(4)静脉给药后归巢至梗死心肌，随后原位分化。(5)分化包括融合独立组件和融合相关组件，经Cre/Iox验证

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.