Department of Gastroenterology, Xin-Hua Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200092, China.
Department of Gastroenterology, Ren-Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 200001, China.
Cell Death Dis. 2020 Aug 7;11(8):639. doi: 10.1038/s41419-020-02832-z.
Liver fibrosis is characterized by the transdifferentiation of hepatic stellate cells (HSCs) to myofibroblasts and poor response to treatment. This can be attributed to the myofibroblast-specific resistance to phenotype reversal. In this study, we complemented miR-16 into miR-16-deficient myofibroblasts and analyzed the global role of miR-16 using transcriptome profiling and generating a pathway-based action model underlying transcriptomic regulation. Phenotypic analysis of myofibroblasts and fibrogenic characterization were used to understand the effect of miR-16 on phenotypic remodeling of myofibroblasts. miR-16 expression altered the transcriptome of myofibroblasts to resemble that of HSCs. Simultaneous targeting of Smad2 and Wnt3a, etc. by miR-16 integrated signaling pathways of TGF-β and Wnt, etc., which underlay the comprehensive regulation of transcriptome. The synergistic effect of miR-16 on the signaling pathways abolished the phenotypic characteristics of myofibroblasts, including collagen production and inhibition of adipogenesis. In vivo, myofibroblast-specific expression of miR-16 not only eliminated mesenchymal cells with myofibroblast characteristics but also restored the phenotype of HSCs in perisinusoidal space. This phenotypic remodeling resolved liver fibrosis induced by chronic wound healing. Therefore, miR-16 may integrate signaling pathways crucial for the fate determination of myofibroblasts. Its global effect induces the reversal of HSC-to-myofibroblast transdifferentiation and, subsequently, the resolution of fibrogenesis. Taken together, these findings highlight the potential of miR-16 as a promising therapeutic target for liver fibrosis.
肝纤维化的特征是肝星状细胞（HSCs）向肌成纤维细胞的转分化和对治疗的反应不良。这可归因于肌成纤维细胞特有的表型逆转抗性。在这项研究中，我们将 miR-16 补充到 miR-16 缺陷型肌成纤维细胞中，并通过转录组谱分析和生成基于途径的转录调控作用模型来分析 miR-16 的全局作用。肌成纤维细胞的表型分析和纤维发生特征用于了解 miR-16 对肌成纤维细胞表型重塑的影响。miR-16 的表达改变了肌成纤维细胞的转录组，使其类似于 HSCs。miR-16 通过同时靶向 Smad2 和 Wnt3a 等，整合了 TGF-β和 Wnt 等信号通路，这是转录组全面调控的基础。miR-16 对信号通路的协同作用消除了肌成纤维细胞的表型特征，包括胶原产生和脂肪生成抑制。在体内，miR-16 在肌成纤维细胞中的特异性表达不仅消除了具有肌成纤维细胞特征的间充质细胞，而且恢复了窦周空间中 HSCs 的表型。这种表型重塑解决了慢性伤口愈合引起的肝纤维化。因此，miR-16 可能整合了对肌成纤维细胞命运决定至关重要的信号通路。其全局作用诱导 HSC 向肌成纤维细胞转分化的逆转，随后纤维发生的解决。综上所述，这些发现强调了 miR-16 作为肝纤维化有希望的治疗靶点的潜力。
