MicroRNA as mediators of angiogenesis & ischemic myocardial repair

描述(申请人提供)：干细胞疗法是一种治疗终末期心力衰竭的推定方法。骨髓间充质干细胞(MSC)可改善心肌内移植后的心功能。我们先前的研究表明，预先编程表达GATA-4(MSCGATA-4)的MSC通过增加MSC的存活和分化，显著加速缺血性心脏修复--AS 以及血管生成。然而，其机制尚不清楚。新近发现的内源性小分子非编码RNAs，microRNAs(MiRs)，在心脏保护和心肌缺血相关的病理过程中发挥着重要作用。我们的初步数据表明，在MSC中过表达GATA-4可以调节几个miRs的表达，然后这些miRs可以从MSC转移到邻近的心肌细胞(CM)。我们提出了以下两个假设：假设1：特定的miRs和miR靶向基因介导了强大的促生存和促血管生成效应。假设2：移植的MSC中的MIR通过缝隙连接和微泡(MVS)转移到邻近的宿主细胞或细胞外环境。这项研究是首次深入探讨GATA-4在MSC中过表达调节特定miRs表达的机制，当这些MSC被移植到缺血心肌中时，进而增强血管生成和心脏保护。这些研究结果应提供证据表明，除分化潜能外，MSC还是心肌保护蛋白和分子修复缺血心肌的重要载体；(Ii)探讨MSC通过MVS将特定分子转移到细胞外液空间，并通过缝隙连接或其他细胞间通道直接进入CM的影响。这些发现不仅可能突出MSCGATA-4介导的血管生成的分子机制，而且可能有助于制定新的缺血治疗策略，并为深入了解心肌重塑的进展提供帮助。

DESCRIPTION (provided by applicant): Stem cell therapy is a putative treatment for end-stage heart failure. Bone marrow-derived mesenchymal stem cells (MSC) improve cardiac function following intramyocardial transplantation. Our previous study indicates that MSC preprogrammed to express GATA-4 (MSCGATA-4), a well-known cardiac transcription factor, significantly accelerate ischemic heart repair - by increasing MSC survival and differentiation, as well as angiogenesis. However, the mechanism is unclear. The recently discovered endogenous class of small non-coding RNAs, microRNAs (miRs), plays an important role in both cardiac protection and pathology associated with myocardial ischemia. Our preliminary data indicate that overexpression of GATA-4 in MSC modulates expression of several miRs which can then transfer from MSC into neighboring cardiomyocytes (CM). We propose the following two hypotheses: Hypothesis 1: Specific miRs and miR targeted genes mediate potent pro-survival and pro-angiogenic effects. Hypothesis 2: miRs in transplanted MSC transfer to neighboring host cells or the extracellular environment via gap junctions and microvesicles (MVs). The proposed study represents the first in- depth attempt to elucidate the mechanism by which GATA-4 overexpression in MSC regulates expression of specific miRs that, in turn, enhance angiogenesis and cardioprotection when these MSC are transplanted into ischemic myocardium. The results of these studies should (i) provide evidence that MSC besides their differentiation potential serve as an important delivery vehicle for cardioprotectve proteins and molecules in repair of ischemic myocardium; (ii) explore the impact of transfer of specific molecules from MSC to the extracellular fluid space via MVs, and directly into CM via gap junctions or other intercellular channels. These findings may not only highlight the molecular mechanisms of MSCGATA-4 - mediated angiogenesis, but may also help formulate a novel therapeutic strategy for ischemia and offer insight into the progression of myocardial remodeling.