Abstract
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis.
Highlights
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure
Hepatic stellate cells (HSCs) extracted from the liver and cultured on plastic for 7–10 days model myofibroblast activation with the appearance of a-Smooth muscle actin (a-SMA), Sex determining region Y-box 9 (SOX9)
While integrin alpha-V was increased consistent with previous findings[18], ITGA11 was more strikingly enhanced following activation of myofibroblasts when it co-precipitated with integrin beta-1 (Supplementary Fig. 1c–e)
Summary
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. In vitro models of liver fibrosis are an imperfect replica of disease in vivo, extraction and culture of HSCs on plastic induces production of collagen-rich extracellular matrix (ECM) characteristic of fibrosis, in part due to the appearance and function of the transcription factor SOX9 (refs 10,11) It is this pathological ECM that causes contracted scarring and increased organ stiffness. Pharmacological inhibition of either pathway lessens the pro-fibrotic myofibroblast phenotype in vitro and attenuates liver fibrosis in vivo These data implicate PAK protein inhibitors as tractable for repositioning from clinical trials in cancer as new anti-fibrotic agents, avoiding the need to target integrin-ECM interactions, which are ubiquitous throughout healthy and diseased tissue
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