Positive feedback loops between fibroblasts and the mechanical environment contribute to dermal fibrosis

Abstract

Dermal fibrosis is characterized by excessive deposition of extracellular matrix in the dermis and affects millions of people worldwide and causes limited movement, disfigurement and psychological distress in patients. Fibroblast dysfunction of plays a central role in the pathogenesis of dermal fibrosis and is controlled by distinct factors. Recent studies support the hypothesis that fibroblasts can drive matrix deposition and stiffening, which in turn can exacerbate the functional dysregulation of fibroblasts. Ultimately, through a positive feedback loop, uncontrolled pathological fibrosis develops. This review aims to summarize the phenomenon and mechanism of the positive feedback loop in dermal fibrosis, and discuss potential therapeutic targets to help further elucidate the pathogenesis of dermal fibrosis and develop therapeutic strategies. In this review, fibroblast-derived compositional and structural changes in the ECM that lead to altered mechanical properties are briefly discussed. We focus on the mechanisms by which mechanical cues participate in dermal fibrosis progression. The mechanosensors discussed in the review include integrins, DDRs, proteoglycans, and mechanosensitive ion channels. The FAK, ERK, Akt, and Rho pathways, as well as transcription factors, including MRTF and YAP/TAZ, are also discussed. In addition, we describe stiffness-induced biological changes in the ECM on fibroblasts that contribute to the formation of a positive feedback loop. Finally, we discuss therapeutic strategies to treat the vicious cycle and present important suggestions for researchers conducting in-depth research.