Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines
Shafie Fazel, Massimo Cimini, Liwen Chen, Shuhong Li, Denis Angoulvant, Paul Fedak, Subodh Verma, Richard D. Weisel, Armand Keating, Ren-Ke Li
Shafie Fazel, Massimo Cimini, Liwen Chen, Shuhong Li, Denis Angoulvant, Paul Fedak, Subodh Verma, Richard D. Weisel, Armand Keating, Ren-Ke Li
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Research Article Cardiology

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

Shafie Fazel, Massimo Cimini, Liwen Chen, Shuhong Li, Denis Angoulvant, Paul Fedak, Subodh Verma, Richard D. Weisel, Armand Keating, Ren-Ke Li

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Figure 2

c-kit+ cells in infarcted myocardium are from the bone marrow.

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c-kit+ cells in infarcted myocardiu...
(A) EPCs from bone marrow chimeric mice carry the GFP transgene. (B) Dual-colored flow cytometry of C57BL/6 (C57) or C57BL/6-GFP bone marrow chimeric mice (C57-GFP) for GFP on the x axis and c-kit on the y axis. In the bone marrow preparation, 74% of c-kit+ cells in the C57-GFP chimeric mice expressed GFP; 74% of c-kit+ cells in the infarcted myocardium in the C57-GFP chimeric mice also expressed GFP. Representative flow cytometry data from 5 independent experiments is shown with results summarized in Table 1. Iso. con, isotype control (C) Confocal micrograph confirming that c-kit+ cells in infarcted myocardium also expressed GFP in chimeric mice (arrow). A GFP+ cell that did not express c-kit (arrowhead) is also visualized in this micrograph. Scale bar: 50 μm. (D) Engraftment of bone marrow–derived cells was minimal when evaluated at 28 days after MI in the bone marrow chimeric mice. Scale bar: 100 μm.