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.

Aging Effects on Cardiac Progenitor Cell Physiology

“…SCF induces CPC migration in a concentration-dependent manner (126,177), and this process is inhibited by c-kit-blocking antibody (177). Gene transfer of SCF in vivo facilitates the functional recovery after myocardial infarction due to the expansion and mobilization of the pool of c-kit-positive CPCs (280,353). HGF, also known as scatter factor, is a paracrine signaling mediator with wide range of biological effects in cell growth and motility.…”

Recent Developments in Cardiovascular Stem Cells

“…Even the identity of the resident CPCs remains unsettled. [39][40][41][42][43] Resident cells expressing the c-kit antigen but not markers of the hematopoietic or mast cells are considered bona fide CPCs sufficient and necessary to repair the damaged myocardium. 40,44 And yet, genetic fate mapping experiments have shown minimal contribution of the c-kit + cells to cardiac myogenesis.…”

c-kit positive cardiac stem cells as a potential candidate for heart repair, developments, challenges and future implications

“…Since c-kit/SCF axis is involved in both proliferation and differentiation 18 , the study only describes the effect of treatment on proliferation of CPCs while its differentiation potential has not been examined. As mentioned in the study that DNMT1 is a maintenance type methyl transferase, the study does not describe whether increased expression of c-kit proto-oncogene will be safe for in vivo transplantations or not.…”

“…In view of the challenges in cell-based therapies, such as selection of appropriate cell types, issues of homing and engraftment along with ethical and regulatory concerns, Yaniz-Galende et al 18 adopted a strategy based on gene therapy to induce recruitment of c-kit + cells and CM re-entry into the cell cycle for the repair of infarcted heart in a rat MI model.…”