Mindin is essential for cutaneous fibrogenesis in a new mouse model of systemic sclerosis

Abstract

Fibrosis is a result of chronically activated fibroblasts leading to the overproduction of extracellular matrix (ECM), causing tissue hardening and loss of organ function. Systemic sclerosis (SSc) is a fibrotic skin disease marked by inflammation, autoimmunity and vasculopathy along with progressive fibrosis of the skin and internal organs. A major bottleneck in understanding the etiology of SSc has been the lack of a holistic animal model that can mimic the human SSc disease. We found that the transcription factor Snail is overexpressed in the epidermis of SSc patients and a transgenic mouse recapitulating this expression pattern is sufficient to induce hallmark clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin in fibrogenesis. Mindin is produced by Snail transgenic skin keratinocytes and aids fibrogenesis by inducing inflammatory cytokine and collagen production in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

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

“…Sca1+ fibroblasts have been reported to express pre-adipocytes markers and contribute to the maintenance of adipose tissue homeostasis 8,11,13 . Consistent with this, in the adult Snail transgenic skin there is a near total absence of dermal white adipose tissue that is replace by collagen 18 .…”

“…To achieve insights into the molecular mechanisms underlying the pro-migratory effect of Mindin on cells we performed GOTERM enrichment analysis on differentially upregulated genes (1715 upregulated genes with P<0.05, FC>1.5 folds) from RNAseq data of Mindin treated fibroblasts 18 . The analysis revealed significant enrichment in biological processes associated with cell migration (41 genes), and positive regulation of cell migration (45 genes) (Figure S2B).…”

“…Despite their important contributions to tumorigenesis, the etiology of these different CAFs remains unanswered. We have previously shown that Snail Tg keratinocytes secrete a factor Mindin in absence of which fibrogenesis and skin inflammation is abrogated 18 . This presented us with a unique opportunity of further understanding the role of Mindin in elucidating the regulation of the functional heterogeneity of fibroblasts in both tissue fibrosis and tumor stroma.…”

“…Nonetheless, the different contributions of various fibroblast sub-populations in response to pro-fibrotic stimuli and the molecular mechanisms to explain their differential activities remain largely unknown. To begin to uncover these molecular mechanism, we utilized a Snail transgenic (Snail Tg) mouse model of skin fibrosis that mimics the overexpression of this transcription factor found in the epidermis of scleroderma (SSc) patients 17,18 . Ectopic expression of Snail is sufficient to induce phenotypes that recapitulates many of the diagnostic features of systemic scleroderma 18 .…”

“…To begin to uncover these molecular mechanism, we utilized a Snail transgenic (Snail Tg) mouse model of skin fibrosis that mimics the overexpression of this transcription factor found in the epidermis of scleroderma (SSc) patients 17,18 . Ectopic expression of Snail is sufficient to induce phenotypes that recapitulates many of the diagnostic features of systemic scleroderma 18 . It is also interesting to note that scleroderma patients also have higher incidence of developing cancers 19 , suggesting that insights into this fibrotic disease would likewise shed light on the factors driving tumorigenesis.…”