The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell Res. 2017 Sep;27(9):1157-1177. doi: 10.1038/cr.2017.103. Epub 2017 Aug 15.
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.
心内膜纤维弹性组织增生症（EFE）是指在新生儿心脏发育过程中，由于心内膜下纤维组织层的重新沉积，导致心室心内膜增厚。EFE 成纤维细胞的起源被认为是出生后心内膜细胞经历异常的内皮到间充质转化（EndMT）。利用诱导型心内膜 Cre 线 Npr3-CreER 和内皮细胞示踪线 Cdh5-CreER 对 EFE 样模型中的心内膜细胞进行遗传谱系追踪，并未发现新生儿心内膜细胞对 EFE 样组织中的成纤维细胞有任何贡献。相反，Wt1-CreER 对胚胎心外膜的谱系追踪表明，心外膜来源的间充质细胞（MCs）是 EFE 成纤维细胞的主要来源。通过 Sox9-CreER 标记 MCs，我们证实胚胎心脏的 MCs 扩增并有助于大多数新生儿 EFE 成纤维细胞的产生。在这个病理过程中，TGFβ 信号通路，成纤维细胞激活的关键介质，在 EFE 样组织中高度上调。通过给予其拮抗剂骨形态发生蛋白 7 靶向 TGFβ 信号通路，有效地减少了 EFE 样模型中成纤维细胞的积累和组织纤维化。我们的研究提供了遗传证据，表明 EFE 样组织中的过多成纤维细胞主要来源于心外膜来源的 MCs 通过心外膜到间充质转化（EpiMT）。这些 EpiMT 衍生的成纤维细胞可能成为 EFE 样组织中的一个潜在治疗靶点。
