Abstract
Mesenchymal progenitor cells play a key role in fibrogenesis. An exciting paper was recently published showed that blister fluid from the skin patients with the autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc) preferentially activated mesenchymal progenitor cells (Taki et al. in Arthritis Rheumatol 72(8):1361–1374, 2020). These data provide new and invaluable insights into the complex interactions in the connective tissue microenvironment that ultimately result in persistent, pathological fibrosis.
Keywords: Microenvironment, Scleroderma, Systemic sclerosis, Coculture, Fibrosis, Myofibroblast, Stem cells
The effector cell of fibrosis is the fibroblast, or, rather, a specialized type of fibroblast termed a myofibroblast. Myofibroblasts excessively produce and remodel the surrounding extracellular matrix (ECM), resulting in the scarring that characterizes fibrotic tissue.
In pathological fibrosis, myofibroblasts appear to arise and persist due to the stable differentiation of mesenchymal progenitor/stem cells (Contreras et al. 2019; Contreras 2020; Tsang et al. 2020). A recent paper (Taki et al. 2020) suggests a basis for examining the mechanism by which this might occur. In a series of key experiments reported in this manuscript, the responses of adipose-derived mesenchymal stem cells (MSC) to blister fluid derived from patients with diffuse systemic sclerosis (dSSc) were examined. Exposure to dSSc blister fluid caused selective MSC activation, relative to healthy dermal fibroblasts. In MSC, dSSc blister fluid induced a myofibroblast gene expression signature, but suppressed vascular repair and adipogenenic gene expression signatures. dSSc blister fluid also caused acquisition of a myofibroblast-associated phenotype, as visualized by enhancement of migration and contractility. Exposure to blister fluid induced microenvironmental factors such as transforming growth factor β, mechanosensing signaling and interleukin-31. Compared to healthy control blister fluid, SSc blister fluid caused significantly increased myofibroblast differentiation (as visualized by, for example, increased alpha-smooth muscle actin, CCN2 expression). The stimulatory effect of SSc blister fluid was antagonized by the pan-TGFβ inhibitory antibody 1D11 and by the mechanostransduction/MRTFA inhibitor CCG-1423.
These data collectively emphasize a critical role of TGFbeta and mechanosignaling in fibrogenesis (Hinz et al. 2019; Leask 2021), and suggest a potential basis for examining the fundamental mechanisms underlying how the microenvironment activates MSC in SSc fibrosis.
Footnotes
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