Cell Stem Cell
Volume 9, Issue 2, 5 August 2011, Pages 131-143
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Article
Erythropoietin Preserves the Endothelial Differentiation Capacity of Cardiac Progenitor Cells and Reduces Heart Failure during Anticancer Therapies

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Summary

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.

Highlights

► STAT3 depletion or DOX used in tumor therapy impair endothelial differentiation of CPC ► Cardiac STAT3 depletion or DOX reduce cardiac EPO levels and CCR2 activation in CPC ► EPO preserves endothelial differentiation by maintaining CCR2 activity on CPC ► STAT3-depleted or DOX-treated hearts can be protected by treatment with synthetic EPO

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These authors contributed equally to this work