Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

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

doi:10.1172/jci45529

Cited by 454 publications

(696 citation statements)

References 41 publications

Supporting

Mentioning

657

Contrasting

Unclassified

Order By: Relevance

“…Earlier studies have reported that epicardial‐activated Wt1 + cells give rise to EPDCs in the heart 20, 21. In rat MI models, EPDCs were observed to localize beneath the epicardium and within the myocardium of the infarct region at 4 weeks after transplantation.…”

Section: Resultsmentioning

confidence: 89%

See 1 more Smart Citation

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

Wang

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF‐1α, Tβ4, VEGF and SDF‐1 expression and decreased CXCL14 expression in hypoxic and serum‐deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF‐1α, Tβ4, VEGF, SDF‐1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial‐derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c‐kit+ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c‐kit+ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy.

show abstract

Section: Resultsmentioning

confidence: 89%

“…Wt1 was expressed in proepicardium and epicardium during the embryonic development and was regard as a marker of activation of the epicardial cells in adult 20. In transgenic mice, GFP + cells were regarded as Wt1 ‐expressing cells.…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

Wang

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…In both zebrafish and mice, the epicardium is activated broadly in response to injury and may secrete paracrine factors and/or undergo EMT to contribute new cells to the area of damage (9,59,60). In addition to further analysis of coronary development, it will be of interest to examine the roles of Dicer and miRNAs during the epicardial response to injury in the adult.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-processing Enzyme Dicer Is Required in Epicardium for Coronary Vasculature Development

Singh

Lü

Massera

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Epicardium-derived cells undergo EMT and differentiate into smooth muscle of the developing coronary vasculature. The role of Dicer in this process is unknown. Results: Dicer mutants displayed impaired epicardial EMT, reduced epicardial cell proliferation, and differentiation into coronary smooth muscle cells. Conclusion: Dicer is essential for epicardium development. Significance: This represents the first evidence for the involvement of Dicer, and by implication miRNAs, in epicardial development.

show abstract

“…Similar to the myocardium, following-injury epicardial cells exhibit morphological changes and reexpress developmental genes including raldh2 and tbx18 (11,12). The epicardium gives rise to myofibroblasts and perivascular cells (13,14), and epicardium-derived perivascular and smooth muscle cells support revascularization of the injured area in zebrafish and mammals (15,16). Following injury, new coronary vessels penetrate the damaged area (5,12,16) where the main source of new coronary endothelium is preexisting endothelium (17).…”

mentioning

confidence: 99%

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Marín-Juez

Marass

Gauvrit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

158

221

View full text Add to dashboard Cite

Zebrafish have a remarkable capacity to regenerate their heart. Efficient replenishment of lost tissues requires the activation of different cell types including the epicardium and endocardium. A complex set of processes is subsequently needed to support cardiomyocyte repopulation. Previous studies have identified important determinants of heart regeneration; however, to date, how revascularization of the damaged area happens remains unknown. Here, we show that angiogenic sprouting into the injured area starts as early as 15 h after injury. To analyze the role of vegfaa in heart regeneration, we used vegfaa mutants rescued to adulthood by vegfaa mRNA injections at the one-cell stage. Surprisingly, vegfaa mutants develop coronaries and revascularize after injury. As a possible explanation for these observations, we find that vegfaa mutant hearts up-regulate the expression of potentially compensating genes. Therefore, to overcome the lack of a revascularization phenotype in vegfaa mutants, we generated fish expressing inducible dominant negative Vegfaa. These fish displayed minimal revascularization of the damaged area. In the absence of fast angiogenic revascularization, cardiomyocyte proliferation did not occur, and the heart failed to regenerate, retaining a fibrotic scar. Hence, our data show that a fast endothelial invasion allows efficient revascularization of the injured area, which is necessary to support replenishment of new tissue and achieve efficient heart regeneration. These findings revisit the model where neovascularization is considered to happen concomitant with the formation of new muscle. Our work also paves the way for future studies designed to understand the molecular mechanisms that regulate fast revascularization.heart regeneration | angiogenesis | revascularization | coronaries | VEGF

show abstract

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

Cited by 454 publications

References 41 publications

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

MicroRNA-processing Enzyme Dicer Is Required in Epicardium for Coronary Vasculature Development

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Contact Info

Product

Resources

About