Preconditioning and re-programming of stem cells for cardiac repair

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DESCRIPTION (provided by applicant): Heart cell therapy using stem cells with myogenic and angiogenic potential or cytokine induced mobilization of bone marrow cells (BMCs) to the site of injury has shown promise. Similarly, ischemic and pharmacological preconditioning has cardioprotective effects. These therapeutic modalities have been adopted to promote de novo myocardial regeneration and reversal of deleterious hemodynamic effects after myocardial infarction (MI). In order to achieve these effects the present study involves transplantation of BMCs together with skeletal myoblasts (SkMs) which will serve mainly as carries of therapeutic genes. Our main hypothesis is that preconditioning and re-programming of cells prior to transplantation would enhance their survival, engraftment and efficacy for cardiac repair. The main aims of our study are; Aim-1) Preconditioning of donor cells for their enhanced survival after transplantation. We posit that treatment of cells by preconditioning mimetics may enhance their tolerance to ischemia via stimulation of cell survival signaling. The preconditioned (PC) cells will also exhibit paracrine effects which will give enhanced host myocyte survival in the infarcted heart. Aim-2) Intramyocardial delivery of non-virally transfected SkMs overexpressing SDF-11 along with transient cytokine therapy for BMCs mobilization for improved heart function. We hypothesized that the elevated SDF-11 levels in the heart will attract circulating CXCR4+ BMCs, egress of which from BM will be distinctly increased after cytokine therapy, to participate in the repair process by angiomyogenesis in the ischemic heart. Aim-3: To activate cytoprotective regulatory pathways in donor SkMs before transplantation. Considering a critical role for Akt and Bcl-2 in cell survival and angiogenesis downstream of angiopoietin-1 (Ang-1)/Tie-2 signaling pathway, we hypothesize that transplantation of SkMs co-overexpressing Ang-1 and Akt or Bcl-2 will give increased cell survival, enhanced angiogenesis, and improved cardiac function. Aim-4 will focus on in vitro re-programming of donor cells for directed differentiation via co-culture with cardiomyocytes to adopt cardiac phenotype after transplantation. The co-culture derived cells will show better engraftment and transdifferentiation after transplantation. Put together, our combined therapeutic approach for preconditioning and re-programming of donor cells before transplantation is expected to give better prognosis in the treatment of ischemically injured myocardium.