Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c-kit+ cells

Abstract

RATIONALE: There is growing evidence that the myocardium responds to injury by recruiting c-kit cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested. OBJECTIVE: To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved. METHODS AND RESULTS: Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic function: an improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c-kit progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/β-catenin pathway induction. CONCLUSIONS: Stem cell factor gene transfer induces c-kit stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction. © 2012 American Heart Association, Inc.