Mechanosensing and fibrosis

Abstract

Tissue injury disrupts the mechanical homeostasis that underlies normal tissue architecture and function. The failure to resolve injury and restore homeostasis gives rise to progressive fibrosis that is accompanied by persistent alterations in the mechanical environment as a consequence of pathological matrix deposition and stiffening. This Review focuses on our rapidly growing understanding of the molecular mechanisms linking the altered mechanical environment in injury, repair, and fibrosis to cellular activation. In particular, our focus is on the mechanisms by which cells transduce mechanical signals, leading to transcriptional and epigenetic responses that underlie both transient and persistent alterations in cell state that contribute to fibrosis. Translation of these mechanobiological insights may enable new approaches to promote tissue repair and arrest or reverse fibrotic tissue remodeling.

Mechano-modulatory synthetic niches for liver organoid derivation

“…Liver disease progression is strongly associated with abnormal tissue architecture and mechanotransduction 15,34,35 . Indeed, as a direct effect of aberrant ECM deposition in the fibrotic liver, tissue stiffness increases in time and severely compromises its function [36][37][38] .…”

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

“…Matrix stiffness, clinically viewed as the end‐stage of organ fibrosis, gradually occurs during the development of tissue fibrosis and increases remarkably in line with deposition, cross‐linking, and reconstruction of the matrix . Recent advances have demonstrated that matrix stiffness has a pivotal role both as the cause and outcome of fibroblast activation in pathological fibrosis . Therefore, targeting the matrix to control tissue repair and fibrosis could be considered as a potential therapeutic strategy.…”

SOX9 is required for kidney fibrosis and regulates NAV3 to control renal myofibroblast function in mice and humans

“…The fibrotic ECM increases organ stiffness. This rigidity perpetuates disease progression 4,5 . Despite renal fibrosis being a significant contributor to patient morbidity and mortality there are no anti-fibrotic drugs currently approved.…”

“…Fibrotic ECM signals via cell-surface integrins to control the cytoskeletal and mechanical properties of myofibroblasts 4,6 . Previously, we identified cytoskeletal alterations in liver myofibroblasts, downstream of integrin β1, mediated through actomyosin signaling via P21-activated kinase (PAK1) and the mechanical transcriptional effector, Yes-associated protein 1 (YAP1) 7,8 .…”