Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines

Abstract

Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/ progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit + cells in the heart. These cells were traced back to a bone marrow origin, using genetic tagging in bone marrow chimeric mice. The recruited c-kit + cells established a proangiogenic milieu in the infarct border zone by increasing VEGF and by reversing the cardiac ratio of angiopoietin-1 to angiopoietin-2. These oscillations potentiated endothelial mitogenesis and were associated with the establishment of an extensive myofibroblast-rich repair tissue. Mutations in the c-kit receptor interfered with the mobilization of the cells to the heart, prevented angiogenesis, diminished myofibroblast-rich repair tissue formation, and led to precipitous cardiac failure and death. Replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype. We conclude that, consistent with their documented role in tumorigenesis, bone marrow c-kit + cells act as key regulators of the angiogenic switch in infarcted myocardium, thereby driving efficient cardiac repair.

Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury

“…The expression of Kit mRNA was 5.4-fold higher 3 d after myocardial infarction than it was 3 d after sham surgery, consistent with published data 12 . Other stem cell markers (Nanog, Zpf42 (also known as Rex-1), Dppa3, and Rif1) showed a small but significant increase in mRNA expression 7 d after myocardial infarction ( Supplementary Fig.…”

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…These effects were only significant in those groups treated with NRG1, suggesting that at least in vivo, NRG1 has a greater vasculogenic effect in comparison with FGF1. While various populations of cardiac progenitor cells have been described, one of the most commonly employed cardiac progenitor markers is c-Kit, which identifies cells that participate in endogenous cardiac repair following MI [39]. Indeed, we identified a dramatic 10-fold increase in the number of c-Kit + /CD45 -progenitor cells 7 days after injection of NRG1-loaded MPs, which coincided with the time when the most drug was released from MPs.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…Concerns about inhibiting KIT were raised recently by studies of the Kit W/W-v mouse, a compound heterozygote in which one allele is deleted and the other has reduced kinase activity. This mouse, when subjected to myocardial infarction, had markedly impaired postmyocardial infarction repair and survival, which was attributed to failure to recruit bone-marrow-derived stem/progenitor cells that are pro-angiogenic to the infarct zone 89,90 . This raises concerns that inhibition of KIT might aggravate pathological remodelling of the heart postmyocardial infarction and prevent repair.…”