Cardiac repair and not regeneration after myocardial infarction: The role and therapeutic utility of thec-kit/SCF pathway

Background. Recent clinical trials have focused on the implantation of adult stem cells, which express the c-kit receptor tyrosine kinase, into infarcted myocardium to regenerate the heart. Cardiomyocyte regeneration remains highly controversial, and the endogenous role of the c-kit+ cells is unknown. I addressed the hypothesis that c-kit activation aids endogenous cardiac repair after myocardial infarction independent of cardiomyocyte regeneration.; Methods. To examine cytokine fluctuations independent of surgical trauma, a closed-chest murine model of cardiac infarction/reperfusion was used. The functional importance of the c-kit pathway was tested in the compound heterozygous c-kit mutant KitW/Kit W-v mice in a model of permanent coronary ligation. To dissect the specific role of bone marrow c-kit+ cells, chimeric c-kit mutant mice with wild type cell bone marrow cells were used. To examine cardiac regeneration by bone marrow stem cells, c-kit bone marrow stem cells from beta-galactosidase transgenic mice were implanted into non-transgenic recipients.; Results. Myocardial infarction lead to c-kit activation and trafficking of c-kit+ endothelial progenitor cells from the bone marrow to the heart. The bone marrow derived c-kit+ cells comprised the majority of the c-kit+ cells in infarcted myocardium, calling into question the existence of the recently identified c-kit+ putative cardiac stem cell. In the presence of a dysfunctional c-kit receptor, coronary ligation lead to rapid cardiac failure. This was attributed to abnormal angiogenesis and abnormal establishment of blood vessel-rich granulation or repair tissue in the infarcted segment. These abnormalities were traced to abnormalities in angiogenic cytokine fluctuations in the infarcted heart. Rescue of the mutant bone marrow with wild type bone marrow cells rescued the cardiomyopathic phenotype by re-establishing post infarction angiogenesis. Implantation of bone marrow stem cells activated the c-kit pathway but did not result in cardiomyogenesis. Over-activation of c-kit pathway improved cardiac repair independent of cardiac regeneration, but resulted in generation of cardiac sarcomas.; Conclusion. Bone marrow c-kit+ cells are recruited to infarcted myocardium where they regulate the balance of angiogenic cytokines enabling efficient cardiac repair. This pathway is amenable to manipulation but a tight dose response to enable efficient cardiac repair but limit tumorigenesis must first be established.