MicroRNA as mediators of angiogenesis & ischemic myocardial repair

描述（由申请人提供）：干细胞疗法是终末期心力衰竭的假定治疗方法。骨髓间充质干细胞（MSC）可改善心肌内移植后的心脏功能。我们之前的研究表明，MSC 预编程表达 GATA-4 (MSCGATA-4)（一种众所周知的心脏转录因子），通过增加 MSC 存活和分化，显着加速缺血性心脏修复，如 以及血管生成。然而，其机制尚不清楚。最近发现的一类内源性小非编码 RNA，即 microRNA (miR)，在心脏保护和与心肌缺血相关的病理学中发挥着重要作用。我们的初步数据表明，MSC 中 GATA-4 的过度表达可调节多种 miR 的表达，然后这些 miR 可以从 MSC 转移到邻近的心肌细胞 (CM) 中。我们提出以下两个假设： 假设 1：特定 miR 和 miR 靶向基因介导有效的促生存和促血管生成作用。假设2：移植的MSC中的miR通过间隙连接和微泡（MV）转移到邻近的宿主细胞或细胞外环境。这项研究首次深入尝试阐明 MSC 中 GATA-4 过表达调节特定 miR 表达的机制，进而在这些 MSC 移植到缺血心肌时增强血管生成和心脏保护作用。这些研究的结果应该 (i) 提供证据表明 MSC 除了其分化潜力之外，还可以作为心脏保护蛋白和分子在修复缺血心肌中的重要递送载体； (ii) 探索特定分子从 MSC 通过 MV 转移到细胞外液空间，并通过间隙连接或其他细胞间通道直接转移到 CM 的影响。这些发现不仅可能强调MSCGATA-4介导的血管生成的分子机制，而且还可能有助于制定一种新的缺血治疗策略，并提供对心肌重塑进展的深入了解。

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.