Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: a new potential target for antifibrotic therapy

Abstract

BackgroundFibrosis may be considered the hallmark of systemic sclerosis (SSc), the end stage triggered by different pathological events. Transforming growth factor-β (TGF-β) and platelet-derived growth factor BB (PDGF-BB) are profibrotic molecules modulating myofibroblast differentiation and proliferation, respectively. There is evidence linking CD248 with these two molecules, both highly expressed in patients with SSc, and suggesting that CD248 may be a therapeutic target for several diseases. The aim of this work was to evaluate the expression of CD248 in SSc skin and its ability to modulate SSc fibrotic process.MethodsAfter ethical approval was obtained, skin biopsies were collected from 20 patients with SSc and 10 healthy control subjects (HC). CD248 expression was investigated in the skin, as well as in bone marrow mesenchymal stem cells (MSCs) treated with TGF-β or PDGF-BB, by immunofluorescence, qRT-PCR, and Western blotting. Finally, in SSc-MSCs, the CD248 gene was silenced by siRNA.ResultsIncreased expression of CD248 was found in endothelial cells and perivascular stromal cells of SSc skin. In SSc-MSCs, the levels of CD248 and α-smooth muscle actin expression were significantly higher than in HC-MSCs. In both SSc- and HC-MSCs, PDGF-BB induced increased expression of Ki-67 when compared with untreated cells but was unable to modulate CD248 levels. After CD248 silencing, both TGF-β and PDGF-BB signaling were inhibited in SSc-MSCs.ConclusionsCD248 overexpression may play an important role in the fibrotic process by modulating the molecular target, leading to perivascular cells differentiation toward myofibroblasts and interfering with its expression, and thus might open a new therapeutic strategy to inhibit myofibroblast generation during SSc.

CD248 and integrin alpha-8 are candidate markers for differentiating lung fibroblast subtypes

“…9a-d), controlling those fibroblasts may lead to the suppression of fibrosis of IPF. Bartis et al and Benedetto et al demonstrated that the reduction of CD248 expression on the fibroblast cell line via siRNA resulted in the reduction of in vitro cell proliferation [23,26], suggesting that CD248 high-ITGA8 low human fibroblast-like cells are possible candidates as therapeutic targets for IPF lungs. As an anti-fibrotic therapy, CD248 blocking peptide as well as siRNA may be effective tools to suppress the Fig.…”

Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review

“…The role of MSCs in injury‐induced tissue fibrosis has been elegantly demonstrated by genetic ablation of Gli1 + MSC, which resulted in the abolishment of fibrosis . Targeting pro‐fibrotic signaling in perivascular stromal cells through inhibition of the C‐type lectin transmembrane receptor Endosialin has recently been shown to inhibit their proliferation and differentiation toward myofibroblasts, which may offer a potential therapeutic target for inhibition of MSC mediated fibrosis .…”

C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

“…CD248 has also been described as being highly expressed in skin samples of patients with systemic sclerosis in comparison to healthy controls . When CD248 expression was silenced by means of siRNA in mesenchymal stem cells from systemic sclerosis patients, TGF‐β and PDGF profibrotic signalling was reduced.…”

“…Idiopathic pulmonary fibrosis patients also display high expression of CD248 in fibroblasts and it may serve as a disease severity marker [139]. CD248 has also been described as being highly expressed in skin samples of patients with systemic sclerosis in comparison to healthy controls [140]. When CD248 expression was silenced by means of siRNA in mesenchymal stem cells from systemic sclerosis patients, TGF-b and PDGF profibrotic signalling was reduced.…”