Targeting Nestin+ hepatic stellate cells ameliorates liver fibrosis by facilitating TβRI degradation.

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Liver fibrosis is a wound-healing response that arises from various aetiologies. The intermediate filament protein, Nestin, has been reported to participate in maintaining tissue homeostasis during wound healing responses. However, little is known about the role Nestin plays in liver fibrosis. This study investigated the function and precise regulatory network of Nestin during liver fibrosis.Nestin expression was assessed via immunostaining and quantitative real-time polymerase chain reaction (qPCR) in fibrotic/cirrhotic samples. The induction of Nestin expression by transforming growth factor beta (TGFβ)-Smad2/3 signalling was investigated through luciferase reporter assays. The functional role of Nestin in hepatic stellate cells (HSCs) was investigated by examining the pathway activity of pro-fibrogenic TGFβ-Smad2/3 signalling and degradation of TGFβ receptor I (TβRI) after interfering with Nestin. The in vivo effects of knocking down Nestin were examined with an adeno-associated virus vector (serotype 6, AAV6) carrying short hairpin RNA (shRNA) targeting Nestin in fibrotic mouse models.Nestin was mainly expressed in activated HSCs and increased with the progression of liver fibrosis. The pro-fibrogenic pathway TGFβ-Smad2/3 induced Nestin expression directly. Knocking down Nestin promoted Caveolin1 (Cav-1)-mediated TβRI degradation, resulting in TGFβ-Smad2/3 pathway impairment and reduced fibrosis marker expression in HSCs. In AAV6-treated murine fibrotic models, knocking down Nestin resulted in decreased levels of inflammatory infiltration, hepatocellular damage, and a reduced degree of fibrosis.The expression of Nestin in HSCs was induced by TGFβ and positively correlated with the degree of liver fibrosis. Knockdown of Nestin decreased activation of TGFβ pathway and alleviated liver fibrosis both in vitro and in vivo. Our data demonstrate a novel role of Nestin in controlling HSC activation in liver fibrosis.

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