Collagens contribute to the mechanical stability of tissues, regulate cell fate and activities. Integrins α1β1, α2β1, α11β1 are the main collagen receptors in skin. Our previous work revealed their individual functions and also demonstrated compensatory mechanisms. We here address the overall significance of integrin-mediated cell-collagen association in vitro and in vivo using mice globally lacking α1β1, α2β1 and α11β1 integrins (tKO). tKO mice are viable and their skin show no striking histological or ultrastructural changes compared to wild type (WT) controls. Dermal tKO fibroblasts fail to adhere to and spread on collagen I, but do so on fibronectin. tKO fibroblasts deposit a structurally aberrant ECM that also negatively impacts spreading of WT fibroblasts. In contrast, the smaller size of tKO fibroblasts grown on their own ECM was partially normalized by plating on WT-ECM. Traction force microscopy revealed significantly reduced traction stress in tKO fibroblasts in response to collagen, along with fewer and smaller focal adhesions and drastically decreased nuclear YAP signals. Phosphorylated (active) discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, was strongly upregulated, but failed to rescue the loss of adhesive and spreading functions of the collagen integrins, indicating compensation of other vital functions of the collagen binding integrins such as providing survival signals. tKO mice showed attenuated dermal fibrosis upon bleomycin with reduced myofibroblast counts, decreased collagen deposition into fibrotic lesions and less densely packed collagen fibrils. Lesions displayed lower active YAP, and nuclei with positive YAP signals were detected in a subset of myofibroblasts only. We conclude that the collagen-binding integrins control the complex ECM environment and assembly of the machinery for force transduction required for myofibroblast survival. These functions are critical for proper assembly of the ECM network, control connective tissue stiffness and homeostasis.

ESDR348 - Collagen-binding integrins are important for orchestrating tissue architecture and fibrotic responses

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING