Abstract 1478: Angiogenesis After a Myocardial Infarction is Regulated by Bone Marrow c-kit+ Cells
Introduction: Clinical trials of bone marrow stem cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism for the benefit is unclear. We examined the endogenous myocardial repair that is dependant on the function of the c-kit receptor, which is expressed on bone marrow stem/progenitor cells and recently identified cardiac stem cells.
Methods and Results: Coronary ligation in C57Bl/6, c-kit mutant KitW/KitW-v, and their wild-type congenic Kit+/+ mice was used to study the role of c-kit in cardiac repair after an MI. MI mobilized c-kit+ VEGF-R2+ Sca-1+ mononuclear cells into the blood-stream within 24 hours of coronary ligation. By 72 hours, an increase in the number of c-kit+ VEGF-R2+ cells was detected in the injured myocardium. Analysis of bone marrow chimeric animals (where ~80% of c-kit+ cells were from the GFP+ donor mouse) demonstrated that at least ~80% of the c-kit+ cells in injured myocardium were from the bone marrow as assessed by GFP expression. The recruited c-kit+ cells established a pro-angiogenic 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 onset of sprouting angiogenesis. Mutations in the c-kit receptor interfered with the mobilization of the c-kit+ VEGF-R2+ cells, prevented angiogenesis, and lead to precipitous cardiac failure and death. Prior replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype in the c-kit mutant mouse.
Conclusion: We conclude that bone marrow c-kit+ cells act as key regulators of the angiogenic switch in infarcted myocardium (similar to their documented role in tumorigenesis), thereby driving efficient cardiac repair.