The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring
The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring
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DOI：
10.1016/j.kint.2017.07.026
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发表时间：
2018-01-01
影响因子：
19.6
通讯作者：
Lan, Hui-Yao
中科院分区：
文献类型：
--
作者：
Tang, Patrick Ming-Kuen;Zhou, Shuang;Lan, Hui-Yao
Src 激活与肾损伤后的纤维形成有关。巨噬细胞-肌成纤维细胞转变是一种新发现的过程，可在肾脏中以 TGF-β/Smad3 依赖性方式局部产生胶原蛋白肌成纤维细胞，从而经历纤维化。巨噬细胞-肌成纤维细胞转变在 Src 介导的肾纤维化中的潜在作用尚不清楚。在通过单细胞分辨率的 RNA 测序进行研究时，我们发现了一个独特的以 Src 为中心的调控基因网络，它是巨噬细胞-肌成纤维细胞转变的关键潜在机制。共鉴定出 501 个与巨噬细胞-肌成纤维细胞转变相关的差异表达基因。然而，Smad3 敲除很大程度上降低了转录组的多样性。更重要的是，抑制Src在体内很大程度上抑制了受损肾脏中输尿管阻塞诱导的巨噬细胞-肌成纤维细胞转变，以及体外骨髓源性巨噬细胞中转化生长因子-β1诱导的细长成纤维细胞样形态、α-平滑肌肌动蛋白表达和胶原蛋白产生。出乎意料的是，我们进一步发现Src作为Smad3的直接靶基因，并且在巨噬细胞-肌成纤维细胞转变过程中在巨噬细胞中特异性上调。因此，巨噬细胞-肌成纤维细胞转变有助于 Src 介导的组织纤维化。因此，靶向Src可能代表巨噬细胞-肌成纤维细胞转变驱动的纤维化疾病的精准治疗策略。
Src activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in the kidney undergoing fibrosis in a TGF-beta/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition. A total of 501 differentially expressed genes associated with macrophage-myofibroblast transition were identified. However, Smad3-knockout largely reduced the transcriptome diversity. More importantly, inhibition of Src largely suppresses ureteral obstruction-induced macrophage-myofibroblast transition in the injured kidney in vivo along with transforming growth factor-beta 1-induced elongated fibroblast-like morphology, alpha-smooth muscle actin expression and collagen production in bone marrow derived macrophages in vitro. Unexpectedly, we further uncovered that Src serves as a direct Smad3 target gene and also specifically up-regulated in macrophages during macrophage-myofibroblast transition. Thus, macrophage-myofibroblast transition contributes to Src-mediated tissue fibrosis. Hence, targeting Src may represent as a precision therapeutic strategy for macrophage-myofibroblast transition-driven fibrotic diseases.