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Transforming growth factor-β (TGFβ) is crucial for liver fibrogenesis and the blunting of TGFβ signalling in hepatic stellate cells (HSCs) or hepatocytes can effectively inhibit liver fibrosis. microRNAs (miRNAs) have emerged as key regulators in modulating TGFβ signalling and liver fibrogenesis. However, the regulation of TGFβ receptor I (TβRI) production by miRNA remains poorly understood. Here we demonstrate that the miR-101 family members act as suppressors of TGFβ signalling by targeting TβRI and its transcriptional activator Kruppel-like factor 6 (KLF6) during liver fibrogenesis. Using a mouse model of carbon tetrachloride (CCl4 )-induced liver fibrosis, we conducted a time-course experiment and observed significant down-regulation of miR-101 in the fibrotic liver as well as in the activated HSCs and injured hepatocytes in the process of liver fibrosis. Meanwhile, up-regulation of TβRI/KLF6 was observed in the fibrotic liver. Subsequent investigations validated that TβRI and KLF6 were direct targets of miR-101. Lentivirus-mediated ectopic expression of miR-101 in liver greatly reduced CCl4 -induced liver fibrosis, whereas intravenous administration of antisense miR-101 oligonucleotides aggravated hepatic fibrogenesis. Mechanistic studies revealed that miR-101 inhibited profibrogenic TGFβ signalling by suppressing TβRI expression in both HSCs and hepatocytes. Additionally, miR-101 promoted the reversal of activated HSCs to a quiescent state, as indicated by suppression of proliferation and migration, loss of activation markers and gain of quiescent HSC-specific markers. In hepatocytes, miR-101 attenuated profibrogenic TGFβ signalling and suppressed the consequent up-regulation of profibrogenic cytokines, as well as TGFβ-induced hepatocyte apoptosis and the inhibition of cell proliferation. The pleiotropic roles of miR-101 in hepatic fibrogenesis suggest that it could be a potential therapeutic target for liver fibrosis.

Background: MicroRNA-21 is important in hepatic fibrosis development, but the mechanism is unclear. Results: MicroRNA-21 is predominantly up-regulated in activated hepatic stellate cells and could form a double negative feedback loop that links fibrogenic machinery. Conclusion:The microRNA-21-mediated loop is a main driving force for hepatic fibrosis progression. Significance: It suggests a mechanism for how microRNA-21 contributes to hepatic fibrosis.Sustained activation of hepatic stellate cells (HSCs) leads to hepatic fibrosis, which is characterized by excessive collagen production, and for which there is no available drug clinically. Despite tremendous progress, the cellular activities underlying HSC activation, especially the driving force in the perpetuation stage, are only partially understood. Recently, microRNA-21 (miR-21) has been found to be prevalently up-regulated during fibrogenesis in different tissues, although its detailed role needs to be further elucidated. In the present study, miR-21 expression was examined in human cirrhotic liver samples and in murine fibrotic livers induced by thioacetamide or carbon tetrachloride. A dramatic miR-21 increase was noted in activated HSCs. We further found that miR-21 maintained itself at constant high levels by using a microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) feedback loop. Disrupting this loop with miR-21 antagomir or AP-1 inhibitors significantly suppressed fibrogenic activities in HSCs and ameliorated liver fibrosis. In contrast, reinforcing this loop with small interfering RNA (siRNA) against PDCD4 promoted fibrogenesis in HSCs. Further analysis indicated that the up-regulated miR-21 promoted the central transforming growth factor-␤ (TGF-␤) signaling pathway underlying HSC activation. In summary, we suggest that the miR-21/PDCD4/AP-1 autoregulatory loop is one of the main driving forces for hepatic fibrosis progression. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy and facilitate drug discovery against hepatic fibrosis.Hepatic fibrosis is a wound healing process in response to chronic liver injuries that leads to unbalanced extracellular matrix (ECM) 3 deposition and resolution. The persistent activation of wound healing responses causes quantitative and qualitative changes in the ECM components and could finally distort liver parenchyma and vascular architecture, which could impair liver function and potentially lead to liver failure and hepatocellular carcinoma. Following liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells that are characterized by the expression of smooth muscle ␣-actin (␣-SMA) and enhanced production of ECM (1). Despite the tremendous progress in understanding the mechanisms during fibrogenesis, the driving force underlying the persistent fibrogenic activities is still only partially understood.Extensive studies have suggested the central role of feedback networks in dictating disease progressi...

Strategies to modify nanoparticles with biological ligands for targeted drug delivery in vivo have been widely studied but met with limited clinical success. A possible reason is that, in the blood circulation, serum proteins could rapidly form a layer of protein "corona" on the vehicle surface, which might block the modified ligands and hamper their targeting functions. We speculate that strategies for drug delivery can be designed based upon elegant control of the corona formation on the vehicle surfaces. In this study, we demonstrate a retinol-conjugated polyetherimine (RcP) nanoparticle system that selectively recruited the retinol binding protein 4 (RBP) in its corona components. RBP was found to bind retinol, and direct the antisense oligonucleotide (ASO)-laden RcP carrier to hepatic stellate cells (HSC), which play essential roles in the progression of hepatic fibrosis. In both mouse fibrosis models, induced by carbon tetrachloride (CCl4) and bile duct ligation (BDL), respectively, the ASO-laden RcP particles effectively suppressed the expression of type I collagen (collagen I), and consequently ameliorated hepatic fibrosis. Such findings suggest that this delivery system, designed to exploit the power of corona proteins, can serve as a promising tool for targeted delivery of therapeutic agents for the treatment of hepatic fibrosis.

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