C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways

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.

Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3′K pathways

“…5 C-kit + cells have been the focus of extensive research. 5,6 While their role as significant source of cardiomyocytes remains controversial, 7,8 c-kit expressing cardiac cells’ ability to differentiate down several cardiac specific lineages including endothelial cells, 7,9 smooth muscle cells, 10 and cardiac myocytes 10,11 makes them an important target for regenerative therapy.…”

Human CardioChimeras: Creation of a Novel ‘Next Generation’ Cardiac Cell

“…Myocardial repair and regeneration research continues to progress on multiple fronts supported by 2 over a decade of cumulative studies despite a recent "whipsaw" movement of controversies related 3 to the terminology and biology of "cardiac stem cells" 30,31 . Although cardiogenic potential of 4 "cardiac stem cells" remains debatable 32,33 , cardioprotective effects have been repeatedly 5 demonstrated by our group and others 13,34,35,36 with "cardiac stem cells", now referred to as cCIC 6 in this report to avoid being misconstrued as cardiogenic cells. Furthermore, cardioprotective 7 effects of cCICs are enhanced by combinatorial delivery with MSCs 6 .…”

G9a histone methyltransferase inhibitor BIX01294 promotes expansion of adult cardiac progenitor cells without changing their phenotype or differentiation potential

“…The results presented in this study are promising, as treatments with BIX01294 did not appear to cause any deleterious effect on the function of CPCs or differentiated cardiac myocytes. Interesting follow‐up studies would be to determine if any of the cytokines that have been characterized for supporting CPC growth in culture – such as stem cell factor, bFGF, EGF and cardiotrophin‐1 – would act in concert for further promoting the expansion of CPCs in cultures. Future studies should also test the capacity of CPCs derived from BIX01294‐treated cardiac tissue to treat the heart in situ , by repairing cardiac tissue that has been damaged in response to injury.…”

“…The results presented in this study are promising, as treatments with BIX01294 did not appear to cause any deleterious effect on the function of CPCs or differentiated cardiac myocytes. Interesting follow-up studies would be to determine if any of the cytokines that have been characterized for supporting CPC growth in culture (6,8,28) such as stem cell factor, bFGF, EGF and cardiotrophin-1would act in concert for further Neither gap junction protein showed any comparative dissimilarities on their pattern of expression among the two culture conditions. Scale bar = 20 lm.…”