Background:Cardiac fibrosis is a lethal outcome of excessive formation of myofibroblasts that are scar-forming cells accumulated after heart injury. It has been reported that cardiac endothelial cells (ECs) contribute to a substantial portion of myofibroblasts through endothelial to mesenchymal transition (EndoMT). Recent lineage tracing studies demonstrate that myofibroblasts are derived from the expansion of resident fibroblasts rather than from the transdifferentiation of ECs. However, it remains unknown whether ECs can transdifferentiate into myofibroblasts reversibly or EndoMT genes were just transiently activated in ECs during cardiac fibrosis.Methods:By using the dual recombination technology based on Cre-loxP and Dre-rox, we generated a genetic lineage tracing system for tracking EndoMT in cardiac ECs. We used it to examine if there is transiently activated mesenchymal gene expression in ECs during cardiac fibrosis. Activation of the broadly used marker gene in myofibroblasts, αSMA (α-smooth muscle actin), and the transcription factor that induces epithelial to mesenchymal transition, Zeb1 (zinc finger E-box–binding homeobox 1), was examined.Results:The genetic system enables continuous tracing of transcriptional activity of targeted genes in vivo. Our genetic fate mapping results revealed that a subset of cardiac ECs transiently expressed αSMA and Zeb1 during embryonic valve formation and transdifferentiated into mesenchymal cells through EndoMT. Nonetheless, they did not contribute to myofibroblasts, nor transiently expressed αSMA or Zeb1 after heart injury. Instead, expression of αSMA was activated in resident fibroblasts during cardiac fibrosis.Conclusions:Mesenchymal gene expression is activated in cardiac ECs through EndoMT in the developing heart, but ECs do not transdifferentiate into myofibroblasts, nor transiently express some known mesenchymal genes during homeostasis and fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblasts by activating mesenchymal gene expression are the major contributors to cardiac fibrosis.

中文翻译：

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心脏纤维化过程中内皮细胞瞬时激活间充质基因表达的无缝基因记录

我们用它来检查心脏纤维化过程中 ECs 中是否存在瞬时激活的间充质基因表达。检查了肌成纤维细胞中广泛使用的标记基因 αSMA（α-平滑肌肌动蛋白）和诱导上皮间质转化的转录因子 Zeb1（锌指 E-box 结合同源框 1）的激活。 结果：遗传系统能够连续追踪体内靶基因的转录活性。我们的遗传命运图谱结果显示，心脏 ECs 的一个子集瞬时表达 结果：遗传系统能够在体内持续追踪靶基因的转录活性。我们的遗传命运图谱结果显示，心脏 ECs 的一个子集瞬时表达 结果：遗传系统能够在体内持续追踪靶基因的转录活性。我们的遗传命运图谱结果显示，心脏 ECs 的一个子集瞬时表达αSMA和Zeb1在胚胎瓣膜形成过程中通过 EndoMT 转分化为间充质细胞。尽管如此，它们对肌成纤维细胞没有贡献，也不会在心脏损伤后瞬时表达αSMA或Zeb1。相反，αSMA 的表达在心脏纤维化过程中在常驻成纤维细胞中被激活。在大人的心里。通过激活间充质基因表达转化为肌成纤维细胞的驻留成纤维细胞是心脏纤维化的主要贡献者。