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. PUBLIC HEALTH RELEVANCE: Coronary artery disease is the most common cause of heart infarction. The cell based therapy using stem cells to cure the infarcted heart appears to be a promising approach. However, several recent studies question the potential of in vivo effect of cell therapy, with low rates of implanted cell survival and engraftment being the suggested causes. The proposed research will attempt myocardial repair by genetic manipulation of stem cells prior to transplantation into infarcted heart in order to increase stem cell survival and engraftment in ischemic microenvironment, and enhances regeneration of infarcted myocardium.
- National Heart, Lung, and Blood Institute
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