Digestive Disease Research Center Core, Medical University of South Carolina, Charleston, SC 29425, USA.
J Cell Sci. 2023 Sep 15;136(18). doi: 10.1242/jcs.261122. Epub 2023 Sep 28.
Liver injury leads to fibrosis and cirrhosis. The primary mechanism underlying the fibrogenic response is the activation of hepatic stellate cells (HSCs), which are 'quiescent' in normal liver but become 'activated' after injury by transdifferentiating into extracellular matrix (ECM)-secreting myofibroblasts. Given that integrins are important in HSC activation and fibrogenesis, we hypothesized that paxillin, a key downstream effector in integrin signaling, might be critical in the fibrosis pathway. Using a cell-culture-based model of HSC activation and in vivo models of liver injury, we found that paxillin is upregulated in activated HSCs and fibrotic livers. Overexpression of paxillin (both in vitro and in vivo) led to increased ECM protein expression, and depletion of paxillin in a novel conditional mouse injury model reduced fibrosis. The mechanism by which paxillin mediated this effect appeared to be through the actin cytoskeleton, which signals to the ERK pathway and induces ECM protein production. These data highlight a novel role for paxillin in HSC biology and fibrosis.
肝损伤导致纤维化和肝硬化。纤维化反应的主要机制是肝星状细胞（HSCs）的激活，HSCs 在正常肝脏中处于“静止”状态，但在损伤后通过转分化为细胞外基质（ECM）分泌的肌成纤维细胞而“激活”。鉴于整合素在 HSC 激活和纤维化发生中很重要，我们假设作为整合素信号下游关键效应物的桩蛋白（paxillin）可能在纤维化途径中起关键作用。我们使用基于细胞培养的 HSC 激活模型和肝损伤的体内模型，发现激活的 HSCs 和纤维化肝脏中桩蛋白上调。桩蛋白的过表达（体外和体内）导致 ECM 蛋白表达增加，而在新型条件性小鼠损伤模型中耗尽桩蛋白可减少纤维化。桩蛋白介导这种作用的机制似乎是通过肌动蛋白细胞骨架，它向 ERK 途径发出信号并诱导 ECM 蛋白的产生。这些数据突出了桩蛋白在 HSC 生物学和纤维化中的新作用。
