Mindin differentially regulates fibroblast subpopulations via distinct members of the Src family kinases during fibrogenesis.

Abstract

Fibrosis is the result of excessive deposition of extracellular matrix (ECM) proteins leading to tissue hardening and loss of organ function. A central player driving fibrosis is the activated fibroblast, which exhibits enhanced migration, proliferation, contraction, and ECM production. However, this raises an interesting puzzle of whether the same fibroblast performs all of the processes that fall under the umbrella term of "activation". Given the heterogeneity of fibroblasts in connective tissues, there are subpopulations of fibroblasts that perform specific functions that are under different regulatory controls. Using a transgenic mouse model of skin fibrosis, we find that the secretion of Mindin from Snail transgenic keratinocytes differentially alters the characteristic of distinct fibroblast subpopulations. Mindin induces migration and inflammatory gene expression of the Sca1+ subpopulation of dermal fibroblasts in a Fyn kinase-dependent manner. On the other hand, Mindin increases the contractile behaviour and collagen production in the papillary CD26+ dermal fibroblasts via c-Src. Moreover, in the context of the fibrotic microenvironment of the tumour stroma, we found that differential responses of resident fibroblasts subpopulations to Mindin extend to the generation of functionally heterogeneous cancer-associated fibroblasts (CAFs). Overall, this work highlights the importance of Mindin in mediating the cellular and signalling heterogeneity of dermal fibroblasts in skin fibrosis and cancer.