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Adult mouse epicardium modulates myocardial injury by secreting paracrine factors.

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.

SUBMITTER: Zhou B

PROVIDER: S-EPMC3083761 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Adult mouse epicardium modulates myocardial injury by secreting paracrine factors.

Zhou Bin B Honor Leah B LB He Huamei H Ma Qing Q Oh Jin-Hee JH Butterfield Catherine C Lin Ruei-Zeng RZ Melero-Martin Juan M JM Dolmatova Elena E Duffy Heather S HS Gise Alexander von Av Zhou Pingzhu P Hu Yong Wu YW Wang Gang G Zhang Bing B Wang Lianchun L Hall Jennifer L JL Moses Marsha A MA McGowan Francis X FX Pu William T WT

The Journal of clinical investigation 20110418 5

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 format ...[more]

PMID: 21505261

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Project description:UnlabelledEpicardium-derived cells (EPDCs) cover the heart surface and can function as a source of both progenitor cells and trophic factors for cardiac repair. Currently, EPDCs cannot be conveniently labeled in vivo to permit imaging and cell tracking. EPDCs formed after myocardial infarction (MI) preferentially take up a perfluorocarbon-containing nanoemulsion (PFC-NE; 130 ± 32 nm) injected 3 days after injury, as measured by (19)F-magnetic resonance imaging ((19)F-MRI). Flow cytometry, immune electron microscopy, and green fluorescent protein (GFP)-transgenic rats (only immune cells, but not epicardial cells, are GFP(+)) demonstrated that PFC-containing EPDCs are nonhematopoietic (CD45(-)/CD11b(-)) but stain positive for markers of mesenchymal stem cells such as platelet-derived growth factor receptor ? (PDGFR-?) CD73, CD105, and CD90. When rhodamine-coupled PFC-NE was used, we found that ?(+) vessel-like structures formed within the infarcted myocardium, comprising approximately 10% of all large vessels positive for smooth muscle actin (SM-actin). The epicardial cell layer, positive for Wilms' tumor 1 (WT-1), PDGFR-?, or KI-67, was shown to be well capillarized (293 ± 78 capillaries per mm(2)), including fenestrated endothelium. Freshly isolated EPDCs were positive for WT-1, GATA-4, KI-67, and FLK-1 (75%), PDGFR-? (50%), and SM-actin (28%) and also exhibited a high capacity for nanoparticle and cell debris uptake. This study demonstrates that EPDCs formed after MI display strong endocytic activity to take up i.v.-injected labeled nanoemulsions. This feature permitted in vivo labeling and tracking of EPDCs, demonstrating their role in myo- and vasculogenesis. The newly discovered endocytic activity permits in vivo imaging of EPDCs with (19)F-MRI and may be used for the liposomal delivery of substances to further study their reparative potential.SignificanceThe present study reports that epicardium-derived cells (EPDCs) formed after myocardial infarction can specifically endocytose nanoparticles in vivo and in vitro. This novel feature permitted in vivo targeting of EPDCs with either a perfluorocarbon-containing or rhodamine-conjugated nanoemulsion to track migration and fate decision of EPDC with (19)F-magnetic resonance imaging and fluorescence microscopy. The liposomal nanoemulsions used in the present study may be useful in the future as a nanomedical device for the delivery of substances to direct cell fate of EPDCs.

Project description:Myeloid differentiation factor 88 (MyD88), an adaptor critical for innate immune function, plays a role in neutrophil recruitment and myocardial injury after transient ischemia. However, how MyD88 signaling modulates neutrophil function and myocardial injury remains unclear. In an in vivo model of neutrophil migration and a chimeric model of MyD88 deletion, we demonstrated that Gr-1-positive (Gr-1(+)) neutrophil migration was significantly decreased by 68% in MyD88-deficient (Myd88(-/-)) mice and by 33% in knockout?wild-type (KO?WT; donor?recipient) chimeric mice, which lacked MyD88 in bone marrow cells but maintained normal MyD88 expression in the heart. This marked attenuation in neutrophil migration was associated with decreased peritoneal neutrophil CXCR2 expression and lower peritoneal KC, a neutrophil chemoattractant, in MyD88(-/-) mice. Moreover, in vitro, KC induces significantly more downregulation of CXCR2 expression in MyD88(-/-) than WT neutrophils. In an in vivo model of myocardial ischemia-reperfusion (I/R) injury, KO?WT chimeric mice had significantly smaller infarct sizes compared with the WT?WT mice. While there was a marked increase in proinflammatory cytokine/chemokine expression in the myocardium following I/R, there was no significant difference between WT?WT and KO?WT mice. In contrast, Gr-1(+) neutrophil recruitment in the myocardium was markedly attenuated in MyD88(-/-) mice. Deletion of Toll-interleukin-1 receptor (TIR)-domain-containing adaptor protein-inducing interferon-?-mediated transcription factor (Trif), another innate immune adaptor, had no effect on the KC-mediated CXCR2 downregulation or on myocardial neutrophil recruitment after I/R. Taken together, these findings suggest that MyD88 signaling is essential for maintaining neutrophil migratory function and chemokine receptor expression. MyD88 signaling in bone marrow-derived circulating cells may play a specific and critical role in the development of myocardial I/R-induced injury.

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Adult mouse epicardium modulates myocardial injury by secreting paracrine factors.

Publications

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors.

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