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

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 6

c-kit dysfunction limits myocardial angiogenesis.

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c-kit dysfunction limits myocardial angiogenesis. (A) VEGF upregulation ...
(A) VEGF upregulation by total heart ELISA following MI is abrogated in KitW/KitW–v mice. n =5 per group. (B) The VEGF in the KitW/KitW–v mouse myocardium is diffusely present and is not localized to the border zone, as quantified in C. n =4 per group. (C) Integrated density value determined by random sampling in 3 ×400 fields per animal. n =4 per group. (D and E) Kit+/+ responds to MI by increasing the ratio of angiopoietin-2 to angiopoietin-1 whereas KitW/KitW–v responds in the opposite fashion. Representative immunoblot is shown. Data are quantified by immunoblotting and densitometry from 4 independent experiments in triplicates. (F) Angiopoietin-2/angiopoietin-1 ratio. **P <0.05 versus day 0 (D0) values; #P <0.05 versus Kit+/+. (G) Number of endothelial cells (blue is CD31) in the cell cycle (red is Ki67) was quantified using confocal microscopy (actin is green) in 5 random ×400 fields in the border zone. n =3 per group per time point. Number of cycling endothelial cells, which appear magenta in color because of overlap of blue CD31 and red Ki67 staining, was higher in the Kit+/+ mice. *P <0.05. hpf, high-power field. (H) Blood vessel density was assessed by CD31 immunohistochemistry in the border zone. (I) Quantification of the number of CD31+ structures from 5 random ×400 fields converted to mm2 showing diminished angiogenic response in KitW/KitW–v mice. ##P <0.01. (J) Blood vessel size quantification showing the KitW/KitW–v mice vessels to be fewer and of larger caliber. n =5 per group.