Wnt11 signaling in stem cell survival and cardiac regeneration

描述(由申请人提供)： Wnt11信号在干细胞存活和心脏再生中的作用体外实验表明，间充质干细胞(MSC)具有向心脏多向分化的潜能。然而，最近的几项研究质疑体内分化的可能性，细胞存活率和植入率低是可能的原因。一些证据表明，非规范的Wnt信号足以在胚胎和成体干细胞群体中诱导心肌细胞承诺。WNT11是非规范WNTS的成员之一，与新生心肌细胞(CM)共培养时，促进循环祖细胞的心脏分化，并促进非心源性组织的心脏分化。我们提出了以下两个假说：假说1。WNT11通过调节GATA-4和抗凋亡miRNAs增加MSC在缺血微环境中的存活和植入；假说2。WNT11在MSC中的过表达促进了缺血心肌的保护、再生和修复。Wnt11信号是MSC依赖的心脏修复的多个方面的关键调节因子的假设是基于我们令人信服的初步发现：(1)Wnt11上调增加MSC在缺血环境中的存活；(2)Wnt11促进MSC转分化为一种心脏表型；(3)Wnt11促进MSC介导的旁分泌因子的释放，从而促进对本地心肌细胞的保护和受损心肌的再生。我们将从分子、细胞和活体器官水平研究Wnt11在MSC介导的心肌梗死修复中的作用及其对心肌血管生成和MSC保护的影响。我们将利用基因转导、激光显微切割、“自杀基因”和一系列电生理技术来研究Wnt11在MSC介导的心肌梗死后再生中的作用。这些研究结果将阐明GATA-4和抗凋亡miRNA在Wnt11介导的MSC存活中的作用，以及(Ii)阐明可能调控MSCWnt11诱导的心肌血管生成的分子机制。用WNT11设计细胞是一个非常令人兴奋的想法。由此产生的分泌因子和miRNAs将允许定向分化和生存。这些数据将对了解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.