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Adult mouse epicardium modulates myocardial injury by secreting paracrine factors
Bin Zhou, … , Francis X. McGowan, William T. Pu
Bin Zhou, … , Francis X. McGowan, William T. Pu
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):1894-1904. https://doi.org/10.1172/JCI45529.
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Research Article Cardiology

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

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Abstract

The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection.

Authors

Bin Zhou, Leah B. Honor, Huamei He, Qing Ma, Jin-Hee Oh, Catherine Butterfield, Ruei-Zeng Lin, Juan M. Melero-Martin, Elena Dolmatova, Heather S. Duffy, Alexander von Gise, Pingzhu Zhou, Yong Wu Hu, Gang Wang, Bing Zhang, Lianchun Wang, Jennifer L. Hall, Marsha A. Moses, Francis X. McGowan, William T. Pu

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Figure 1

Epicardium is quiescent in the normal postnatal heart.

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Epicardium is quiescent in the normal postnatal heart.
(A) Expression of...
(A) Expression of WT1 and Wt1-driven fusion protein epitope GFP (Wt1GFPCre/+) in fetal epicardium. White arrowheads, epicardial expression of GFP and WT1; yellow arrows, subepicardial migrating EPDC still expressing WT1 and GFP; white arrows, blood cells inside myocardium. (B) Expression of WT1 or GFP (white arrowheads) in postnatal epicardium. (C) WT1 was also expressed in postnatal human epicardium (red arrowhead). (D) Quantitation of WT1+ or GFP+ epicardial cells in Wt1GFPCre/+ hearts (n = 3–6). (E) Experimental outline for genetic fate mapping in normal postnatal heart using Wt1CreERT2/+;Rosa26mTmG/+ mice. Tam irreversibly changed expression of membrane-localized RFP to membrane-localized GFP (arrowheads). In normal mice, Cre activity was strictly tam dependent. Scale bars: 100 μm; 20 μm (C, right).

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