SAT0313 Role of CD248 molecule as potential regulator of trans-differentiation toward myofibroblasts of perivascular stromal cells in systemic sclerosis patients
Authors: P Di Benedetto, P Ruscitti, V Liakouli, F Carubbi, O Berardicurti, A Lizzi, S Di Bartolomeo, G D'Andrea, R Giacomelli, P Cipriani
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The microvascular damage is a pivotal event in the pathogenesis of Systemic Sclerosis (SSc) and, after injury, both endothelial cells (ECs) and pericytes might trans-differentiate toward myofibroblast, responsible of fibrosis. Platelet-derived growth factor B (PDGFB) and transforming growth factorβ (TGFβ) play a key role in SSc pathogenesis. PDGFB is a potent mitogen for myofibroblasts, while TGFβ stimulate myofibroblast activation, including alpha smooth muscle actin (αSMA) expression. A key regulator of PDGFB and TGFβ signaling may be the CD248, a trans-membrane receptor required for proliferation and migration of pericytes and fibroblasts. It has been showed that, in an animal model of kidney fibrosis, the genetic deletion of CD248 modulates the response of renal pericytes to injury, by reducing the differentiation of myofibroblasts. The expression of CD248 is required for TGFβ-induced αSMA expression in pericytes and CD248 enhances the PDGFB pathway, mediating the proliferation and migration of perivascular cells. <h3>Objectives</h3> The aim of this work was to evaluate the expression of CD248, in SSc skin biopsies and its possible role in perivascular stromal cells proliferation, responsible to myofibroblast trans-differentiation, during SSc. <h3>Methods</h3> After ethical approval, skin biopsies and bone marrow mesenchymal stem cells (MSCs) were collected from 20 diffuse SSc patients and 10 healthy control (HC). CD248 expression was investigated in the skin, and in isolated MSCs treated with TGFβ or PDGFB, by immunofluorescence, qRT-PCR and western. Furthermore, we silenced CD248 in SSc-MSCs, to confirm the role of this molecule in TGFβ- or PDGFB-signaling modulation. <h3>Results</h3> CD248 expression in SSc skin was significantly higher when compared with HC skin. In particular, an increased expression of CD248 was found in ECs, stromal fibroblast and perivascular like stromal cells, co-expressing CD90, a marker of un-differentiated MSCs. Furthermore, in both, HC- and SSc-MSCs, TGFβ treatment induced a significant reduction of CD248 mRNA expression, in parallel with a significant increase of αSMA and a decrease of proliferation (ki67), when compared with untreated- (UT-) cells. Interestingly, the ability of TGFβ to inhibit CD248 expression in HC-MSCs was significantly higher than SSc-MSCs, suggesting that local environment in SSc patients affect TGFβ ability to suppress CD248 expression in SSc-MSCs. After treatment with PDGFB in both SSc- and HC-MSCs, CD248 expression was not affected, while significant reduction of αSMA and an increased expression of Ki67 was observed compared with UT-cells. After silencing of CD248 in SSc-MSCs, both TGFβ and PDGFB signaling were inhibited. <h3>Conclusions</h3> CD248 over-expression may play an important role in tissue fibrosis by modulating the pericytes to myofibroblast trans-differentiation, via regulation of both PDGFB and TGFβ signaling, during SSc. <h3>References</h3> Cipriani P et al, J Rheumatol 2016. Smith SW et al, Nephron 2015. <h3>Disclosure of Interest</h3> None declared