Wnt11 signaling in stem cell survival and cardiac regeneration

描述（由申请人提供）： 间充质干细胞（mesenchymal stem cells，MSC）具有向心脏多系分化的潜能。然而，最近的几项研究质疑体内分化的潜力，细胞存活率低和植入率低是可能的原因。一些证据表明，非经典Wnt信号足以诱导胚胎和成体干细胞群体中的心肌细胞定型。Wnt 11是非经典Wnt的成员之一，在与新生儿心肌细胞（CM）共培养时增强循环祖细胞的心脏分化，并促进非心源性组织中的心脏分化。我们提出以下两个假设：假设1。Wnt 11通过调节加塔-4和抗凋亡miRNA增加MSC在缺血微环境中的存活和植入;假设2. Wnt 11在MSC中的过表达增强缺血心肌的保护、再生和修复。Wnt 11信号是MSC依赖性心脏修复多个方面的关键调节因子的假设基于我们令人信服的初步发现：（1）Wnt 11的上调增加了MSC在缺血环境中的活力;（2）Wnt 11促进MSC转分化为心脏表型，（3）Wnt 11促进MSC介导的旁分泌因子的释放，促进心肌细胞的保护和损伤心肌的再生。我们将从分子、细胞和体内器官水平系统地探讨Wnt 11在MSC介导的心肌梗死修复中的作用。我们将利用基因转导、激光显微切割、“自杀基因”等一系列电生理技术研究Wnt 11对MSC介导的梗死心肌再生的作用。这些研究的结果应该（i）阐明加塔-4和抗凋亡miRNA在Wnt 11介导的MSC存活中的作用，和（ii）阐明可能调节MSCWnt 11诱导的肌血管生成的分子机制。用Wnt11工程化细胞是一个非常令人兴奋的想法。所产生的分泌因子和miRNA将允许定向分化和存活。这些数据将对理解Wnt11介导的心脏修复信号通路产生深远的影响。

DESCRIPTION (provided by applicant): Wnt11 signaling in stem cell survival and cardiac regeneration The potential of mesenchymal stem cells (MSC) to adopt cardiac multilineage differentiation has been shown in vitro. However, several recent studies question the potential of in vivo differentiation, with low rates of cell survival and engraftment being the suggested causes. Several lines of evidence demonstrate that noncanonical Wnt signaling is sufficient to induce cardiomyocytic commitment in both embryonic and adult stem cell populations. Wnt11, one member of the non-canonical Wnts, enhances cardiac differentiation of circulating progenitor cells upon co-culture with neonatal cardiomyocytes (CM) and promotes cardiac differentiation in noncardiogenic tissue. We propose the following two hypotheses: Hypothesis 1. Wnt11 increases MSC survival and engraftment in ischemic microenvironment via regulation of GATA-4 and anti- apoptotic miRNAs; Hypothesis 2. Overexpression of Wnt11 in MSC enhances protection, regeneration and repair of ischemic myocardium. The hypothesis that Wnt11 signaling is a key regulator of multiple aspects of MSC-dependent cardiac repair is based on our convincing preliminary findings: (1) upregulation of Wnt11 increased the viability of MSC in an ischemic environment; (2) Wnt11 promoted MSC transdifferentiation into a cardiac phenotype, (3) Wnt11 augmented release of MSC-mediated paracrine factors which facilitated the protection of native cardiomyocytes and regeneration of damaged myocardium. We will systematically explore the role of Wnt11 on MSC-mediated repair of infracted heart by examining its effect on myoangiogenesis and MSC protection at the molecular, cellular and in vivo organ levels. We will use gene transduction, laser micro-dissection, "suicide gene", and series electrophysiologic techniques to study the action of Wnt11 on MSC mediated regeneration of infarcted myocardium. The results of these studies should (i) clarify the role of GATA-4 and anti-apoptotic miRNA in Wnt11 mediated MSC survival, and (ii) elucidate the molecular mechanisms which may regulate MSCWnt11 induced myoangiogenesis. Engineering cells with Wnt11 is quite exciting idea. The resultant secretory factors and miRNAs will allow directed differentiation and survival. These data will have far- reaching impact upon understanding of Wnt11 mediated signaling pathway in cardiac repair.