title: 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.
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shafie
authors.initials: S
authors.lastname: Fazel
authors.forename: Massimo
authors.initials: M
authors.lastname: Cimini
authors.forename: Liwen
authors.initials: L
authors.lastname: Chen
authors.forename: Shuhong
authors.initials: S
authors.lastname: Li
authors.forename: Denis
authors.initials: D
authors.lastname: Angoulvant
authors.forename: Paul
authors.initials: P
authors.lastname: Fedak
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D018183:Transplantation Chimera; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D011993:Recombinant Fusion Proteins; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2