Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies

Cell Stem Cell. 2011 Aug 5;9(2):131-43. doi: 10.1016/j.stem.2011.07.001.

Abstract

Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Animals
  • Antigens, Ly / metabolism
  • Antineoplastic Agents / adverse effects*
  • Capillaries / drug effects
  • Capillaries / pathology
  • Cell Differentiation / drug effects*
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Erythropoietin / pharmacology*
  • Erythropoietin / therapeutic use
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Gene Deletion
  • Heart Failure / chemically induced
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Heart Function Tests / drug effects
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Myocardium / pathology*
  • Organ Specificity / drug effects
  • Pericytes / cytology
  • Pericytes / drug effects
  • Receptors, CCR2 / metabolism
  • Receptors, Erythropoietin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Survival Analysis
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antigens, Ly
  • Antineoplastic Agents
  • Ccr2 protein, mouse
  • Ly6a protein, mouse
  • Membrane Proteins
  • Receptors, CCR2
  • Receptors, Erythropoietin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Erythropoietin
  • Doxorubicin
  • Vascular Endothelial Growth Factor Receptor-2

Associated data

  • GEO/GSE30306