Abstract
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.
Highlights
Liver fibrosis, a serious health problem worldwide, is induced by chronic liver injuries, which often lead to the development of hepatocellular carcinoma[1]
Liver fibrosis is characterized by the transdifferentiation of hepatic stellate cells (HSCs), a kind of adipogenic cells, toward myofibroblasts[2]
After validating the alterations in the transcriptome (Supplementary Fig. S7), the filtered genes were categorized by hierarchical clustering (Fig. 1a) and function (Supplementary Table S2). (1) Adipogenic genes, which characterizes HSCs, were increased after the administration of miR-16. (2) miR-16-regulated cytokines, collagens, and matrix metallopeptidases showed a rebalancing of extracellular matrix (ECM) production and zymohydrolysis, thereby inactivating the myofibroblasts and
Summary
A serious health problem worldwide, is induced by chronic liver injuries (hepatitis, alcoholism, cholestasis, etc.), which often lead to the development of hepatocellular carcinoma[1]. Multiple signaling pathways act in concert to enable this phenotypic transition[2,3]. In contrast to most agents that act through single target, miRNA demonstrates a unique pattern, mainly multiple targeting, of gene regulation[4]. This pleiotropic effect highlights the importance of miRNAs in the phenotypic determination of various types of cells[5,6,7,8,9]. Among phenotype-regulating miRNAs, miR-16 is the most extensively explored one ever since its identification in 200510,11, and serves as internal control of miRNA analysis for an universal and relative stable expression12. miR-
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