The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.
Centre for Ageing Research Program, Queensland University of Technology, Woolloongabba, QLD, Australia.
Nat Commun. 2021 May 7;12(1):2564. doi: 10.1038/s41467-021-22717-9.
Endothelial to mesenchymal transition (EndMT) is a leading cause of fibrosis and disease, however its mechanism has yet to be elucidated. The endothelium possesses a profound regenerative capacity to adapt and reorganize that is attributed to a population of vessel-resident endovascular progenitors (EVP) governing an endothelial hierarchy. Here, using fate analysis, we show that two transcription factors SOX9 and RBPJ specifically affect the murine EVP numbers and regulate lineage specification. Conditional knock-out of Sox9 from the vasculature (Sox9/Cdh5-Cre RosaYFP) depletes EVP while enhancing Rbpj expression and canonical Notch signalling. Additionally, skin wound analysis from Sox9 conditional knock-out mice demonstrates a significant reduction in pathological EndMT resulting in reduced scar area. The converse is observed with Rbpj conditionally knocked-out from the murine vasculature (Rbpj/Cdh5-CreER RosaYFP) or inhibition of Notch signaling in human endothelial colony forming cells, resulting in enhanced Sox9 and EndMT related gene (Snail, Slug, Twist1, Twist2, TGF-β) expression. Similarly, increased endothelial hedgehog signaling (Ptch1/Cdh5-CreER RosaYFP), that upregulates the expression of Sox9 in cells undergoing pathological EndMT, also results in excess fibrosis. Endothelial cells transitioning to a mesenchymal fate express increased Sox9, reduced Rbpj and enhanced EndMT. Importantly, using topical administration of siRNA against Sox9 on skin wounds can substantially reduce scar area by blocking pathological EndMT. Overall, here we report distinct fates of EVPs according to the relative expression of Rbpj or Notch signalling and Sox9, highlighting their potential plasticity and opening exciting avenues for more effective therapies in fibrotic diseases.
内皮到间质转化（EndMT）是纤维化和疾病的主要原因，但它的机制尚未阐明。内皮具有深刻的再生能力，以适应和重组，这归因于一群血管驻留的血管内祖细胞（EVP），它们控制着内皮层次结构。在这里，我们使用命运分析表明，两个转录因子 SOX9 和 RBPJ 特异性地影响小鼠 EVP 的数量并调节谱系特化。血管中的 Sox9 条件性敲除（Sox9/Cdh5-Cre RosaYFP）耗尽 EVP，同时增强 Rbpj 表达和经典 Notch 信号。此外，来自 Sox9 条件性敲除小鼠的皮肤伤口分析表明，病理性 EndMT 显著减少，导致疤痕面积减少。相反，在血管中从 Rbpj 条件性敲除的小鼠（Rbpj/Cdh5-CreER RosaYFP）或抑制人内皮集落形成细胞中的 Notch 信号观察到相反的结果，导致 Sox9 和 EndMT 相关基因（Snail、Slug、Twist1、Twist2、TGF-β）表达增强。同样，增加内皮 Hedgehog 信号（Ptch1/Cdh5-CreER RosaYFP），上调经历病理性 EndMT 的细胞中 Sox9 的表达，也会导致过多的纤维化。向间充质命运转化的内皮细胞表达增加的 Sox9、减少的 Rbpj 和增强的 EndMT。重要的是，通过在皮肤伤口上局部施用 Sox9 的 siRNA，可以通过阻断病理性 EndMT 来显著减少疤痕面积。总的来说，在这里我们报告了根据 Rbpj 或 Notch 信号和 Sox9 的相对表达，EVP 的不同命运，突出了它们的潜在可塑性，并为纤维化疾病的更有效治疗开辟了令人兴奋的途径。
