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Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines
Shafie Fazel, … , Armand Keating, Ren-Ke Li
Shafie Fazel, … , Armand Keating, Ren-Ke Li
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1865-1877. https://doi.org/10.1172/JCI27019.
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Research Article Cardiology Article has an altmetric score of 9

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

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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 1

c-kit+ cells increase in infarcted myocardium.

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                  c-kit+
                  cells increase in infarcted ...
(A) Quantification of EPCs over a time course after MI in wild-type mice. Upperpanels, flow cytometry for VEGFR2+ cells. Lower panels, in vitro splenocyte fibronectin (Fib.) adhesion, acetylated LDL uptake (Ac-LDL), and lectin-binding assay results. Total number of cells was calculated by multiplying percentage of positive cells by total number of cells isolated from both tibia and femur of 1 mouse. n = 3–5 per time point. *P < 0.05 compared to day 0 values. (B) MI causes an increase in VEGFR2+c-kit+Sca-1+ subset of PBMCs. (C) Increase of c-kit+ cells is specific to the injured myocardium (arrowhead). Seven days after MI, c-kit+ cells were not detected in other organs and the peripheral circulation. Gray, isotype control; red, c-kit. (D and E) The c-kit+ cells detected after MI in the heart were homogeneously VEGFR2+ but heterogeneous with respect to CD45 expression. –ve con, negative control. (F) Quantification of the number of c-kit+ cells. Lowerpanel shows that the majority of the c-kit+ cells in the heart were CD45–. n = 3 per time point. (G–J) Confocal microscopic images. (G) c-kit+ cells visualized at the infarct border zone both as isolated cells (arrowheads) and in clusters (arrow). Scale bar: 100 μm. (H) The majority of the c-kit+ cells did not express CD45 (arrowhead) although some of the clusters contained CD45-expressing cells (arrow). Scale bar: 50 μm. (I) c-kit+ cells present in the clusters are shown to express Ki67 cell cycling–associated nuclear antigen. Scale bar: 10 μm. (J) c-kit+ cells in the cell cycle (arrowhead) did not coexpress CD45 (arrow). Scale bar: 10 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 6 patents
Referenced in 1 clinical guideline sources
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