Background/Purpose:

Microvascular rarefaction and tissue fibrosis are the hallmarks of Systemic Sclerosis (SSc). CD248, also known as endosialin, is a transmembrane glycoprotein expressed on key effector cells within the stroma of fibrotic tissue, including pericytes and fibroblast (FBs). The functional role of CD248 during fibrotic process is largely unknown, although it has been reported that in the experimental models of liver and kidney fibrosis, CD248−/− mice are protected from myofibroblast accumulation and capillary rarefaction, probably inhibiting pericytes differentiation toward αSMA+ myofibroblasts. On these bases, CD248 may be considered an attractive therapeutic target in the pathologic processes in which vascular damage and fibrosis are strongly joined, as observed in SSc. The aim of this work was to investigate the expression of CD248 isoforms, in dermal fibroblasts and evaluate the functional contribute of this molecule to exacerbate the microvascular damage during SSc.

Methods:

After ethical approval, skin biopsies were collected from SSc-patients and healthy controls (HC). CD248 expression was investigated in the skin and in cultured FBs before and after TGFβ treatment, by immunohistochemistry, qRT-PCR and western-blot. Additionally, we assessed the role of CD248 expression on angiogenesis by employing endothelial cel/SSc-FBs organotypic cocultures where FBs were treated or not with lentiviral induced CD248 short-hairpin RNAs delivery.

Results:

CD248 expression was increased in perivascular cells and fibroblasts in SSc-skin. We identified 2 different isoforms of CD248 molecule, one short isoform, which has been generally correlated with the activated status of CD248, and one long isoform. Both the isoforms were significantly increased in SSc-FBs compared to HC-FBs, with the short isoform was not expressed at all in HC-cells. TGFβ treatment of SSc-FBs induced a significant increase of CD248 expression. Functionally, SSc-FBs, SSc-FBs, overexpressing CD248, suppressed angiogenesis in the organotypic model and, after silencing this molecule, the angiogenic phenotype was rescued.

Conclusion:

The over-expression of short isoform of CD248, increased after TGFβ treatment, may play a role in fibrotic process by modulating the molecular pathways leading to dermal FBs differentiation toward myofibroblast, responsible of the impaired extracellular matrix production and interfering with endothelial cells tube formation. The CD248 silencing may prevent these angiogenic alterations. Future study, targeting CD248, may open new therapeutic strategy to inhibit both myofibroblasts generation and microvascular damage.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/myofibroblast-cells-expression-of-cd248-may-contribute-to-exacerbate-microvascular-damage-during-systemic-sclerosis/