Abstract
A recent phase I clinical trial (SCIPIO) has shown that autologous c-kit+ cardiac progenitor cells (CPCs) improve cardiac function and quality of life when transplanted into patients with ischemic heart disease. Although c-kit is widely used as a marker of resident CPCs, its role in the regulation of the cellular characteristics of CPCs remains unknown. We hypothesized that c-kit plays a role in the survival, growth, and migration of CPCs. To test this hypothesis, human CPCs were grown under stress conditions in the presence or absence of SCF, and the effects of SCF-mediated activation of c-kit on CPC survival/growth and migration were measured. SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions. In addition, SCF significantly promoted CPC migration in vitro. Furthermore, the pro-survival and pro-migratory effects of SCF were augmented by c-kit overexpression and abrogated by c-kit inhibition with imatinib. Mechanistically, c-kit activation in CPCs led to activation of the PI3K and the MAPK pathways. With the use of specific inhibitors, we confirmed that the SCF/c-kit-dependent survival and chemotaxis of CPCs are dependent on both pathways. Taken together, our findings suggest that c-kit promotes the survival/growth and migration of human CPCs cultured ex vivo via the activation of PI3K and MAPK pathways. These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit.
Highlights
The adult mammalian heart has long been considered a post-mitotic organ that is incapable of regeneration
Our results indicate that activation of c-kit by Stem cell factor (SCF) promotes the growth, survival and migration of human Cardiac Progenitor Cells (CPCs), and that these effects are mediated by the phosphoinositol 3 kinase (PI3K)-AKT and MEK-ERK pathways
We examined if SCF, besides acting as a mitogen, can prevent apoptosis induced by serum depletion in CPCs
Summary
The adult mammalian heart has long been considered a post-mitotic organ that is incapable of regeneration. C-Kit in Human Cardiac Progenitor Cells (CPCs) populations have been reported in adult myocardium These stem cell populations were initially identified based on their expression of common stem cell antigens, such as c-kit [4, 5] and Sca-1 [6, 7], or on their ability to efflux a fluorescent dye, Hoechst 33342 (“side population”) [8, 9] or to form spherical bodies (“cardiospheres”) under specific culture conditions [10, 11]. In addition to its role in tumorigenesis, studies in c-kit mutant mice have shown that it plays a critical role in regulating survival, proliferation, differentiation, and migration of various cell types, including mast cells [34, 35], melanocytes [36, 37], germ cells [38, 39] and vascular endothelial cells [40]. Our results indicate that activation of c-kit by SCF promotes the growth, survival and migration of human CPCs, and that these effects are mediated by the PI3K-AKT and MEK-ERK pathways
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