Abstract
Endocardial fibroelastosis (EFE) refers to the thickening of the ventricular endocardium as a result of de novo deposition of subendocardial fibrous tissue layers during neonatal heart development. The origin of EFE fibroblasts is proposed to be postnatal endocardial cells that undergo an aberrant endothelial-to-mesenchymal transition (EndMT). Genetic lineage tracing of endocardial cells with the inducible endocardial Cre line Npr3-CreER and the endothelial cell tracing line Cdh5-CreER on an EFE-like model did not reveal any contribution of neonatal endocardial cells to fibroblasts in the EFE-like tissues. Instead, lineage tracing of embryonic epicardium by Wt1-CreER suggested that epicardium-derived mesenchymal cells (MCs) served as the major source of EFE fibroblasts. By labeling MCs using Sox9-CreER, we confirmed that MCs of the embryonic heart expand and contribute to the majority of neonatal EFE fibroblasts. During this pathological process, TGFβ signaling, the key mediator of fibroblasts activation, was highly upregulated in the EFE-like tissues. Targeting TGFβ signaling by administration of its antagonist bone morphogenetic protein 7 effectively reduced fibroblast accumulation and tissue fibrosis in the EFE-like model. Our study provides genetic evidence that excessive fibroblasts in the EFE-like tissues mainly originate from the epicardium-derived MCs through epicardial to mesenchymal transition (EpiMT). These EpiMT-derived fibroblasts within the EFE-like tissues could serve as a potential therapeutic target.
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Acknowledgements
We thank Baojin Wu, Guoyuan Chen, Zhonghui Weng and Aimin Huang for the animal husbandry; and Wei Bian for his technical help. We thank Shanghai Biomodel Organism Science & Technology Development Co., Ltd for mouse generation. We thank Ralf Adams at Max Plank Institute for providing the Cdh5-CreER mouse line and Hongkui Zeng for reporter lines. We also thank other members of our laboratory for insightful discussion and technical help throughout this study. This work was supported by Strategic Priority Research Program of the Chinese Academy of Sciences (CAS, XDB19000000), The National key Research & Development Program of China (2017YFC1001300 and 2016YFC1300600), National Natural Science Foundation of China (91639302, 31625019, 31571503, 31501172, 31601168), Youth Innovation Promotion Association of CAS (2015218), Key Project of Frontier Sciences of CAS (QYZDB-SSW-SMC003), International Cooperation Fund of CAS, National Program for Support of Top-notch Young Professionals, Shanghai Science and Technology Commission (14JC1407300, 17ZR1449600, 17ZR1449800), Shanghai Yangfan Project (15YF1414000, 16YF1413400) and Rising-Star Program (15QA1404300), China Postdoctoral Science Foundation (2015M581669, 2016T90387, 2016LH0042), President Fund of Shanghai Institutes for Biological Sciences (SIBS), Astrazeneca, Boehringer Ingelheim, Sanofi-SIBS Fellowship and Research Grants Council of Hong Kong (24110515, 14111916).
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Supplementary information, Figure S1
Endocardial fibroelastosis (EFE) tissue lining the left ventricle after heterotopic heart transplantation. (PDF 1240 kb)
Supplementary information, Figure S2
Npr3-CreER labeled endocardial or epicardial cells do not contribute to fibroblasts in native hearts. (PDF 1700 kb)
Supplementary information, Figure S3
Sox9 is expressed in cushion mesenchymal cells and epicardiai cells at E10.5 - E11.5. (PDF 1205 kb)
Supplementary information, Figure S4
Sox9-CreER labels embryonic cardiac mesenchymal cells and epicardial cells, but not endothelial cells. (PDF 1263 kb)
Supplementary information, Figure S5
Sox9-CreER does not label hematopoietic cells. (PDF 747 kb)
Supplementary information, Figure S6
Embryonic endocardial cells contribute to fibroblasts in the native hearts. (PDF 1181 kb)
Supplementary information, Figure S7
FSP1 is expressed in leucocytes. (PDF 1018 kb)
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Zhang, H., Huang, X., Liu, K. et al. Fibroblasts in an endocardial fibroelastosis disease model mainly originate from mesenchymal derivatives of epicardium. Cell Res 27, 1157–1177 (2017). https://doi.org/10.1038/cr.2017.103
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DOI: https://doi.org/10.1038/cr.2017.103
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