Systemic sclerosis (SSc), also known as scleroderma is a chronic autoimmune disease where patients suffer from skin hardening and thickening as well as fibrosis of many internal organs, including the lungs. Patients also experience a loss of vasculature and an alteration of vasculature architecture. There is evidence that endothelial cells transitioning into mesenchymal cells (known as EndMT) may be one of the mechanisms that contributes to disease progression. Thus, this study aims to elucidate if EndMT does play a role in SSc using endothelial lineage tracing experiments with Cdh5-creERt2/ROSA-YFP mice, where endothelial cells are labelled with YFP. In addition, previous data from our lab suggests that a reduction in Sox9 signalling in the endothelium can decrease the amount of fibrosis observed when mice are recovering from wounding. Thus, the second aim of our study is to determine if a vascular Sox9 knockout mouse (Sox9lox/lox Cdh5-creERt2/ROSA-YFP) will display reduced fibrosis in an SSc setting. Preliminary results indicate that EndMT may not actually be the driving force in SSc pathogenesis, as increased numbers of endothelial cells in transition (defined as YFP+/a-smooth muscle actin+/CD31+) or endothelial cells that have fully transitioned (defined as YFP+/ a-smooth muscle actin+/CD31-) were not evident in immunofluorescent staining of the skin (n=4) and the lungs (n=6). In addition, when Sox9KO mice with SSc were evaluated, there was no reduction in fibrosis observed on slides stained with Masson’s Trichrome in both the skin (n=6) and the lungs (n=6-9), indicating vascular Sox9 may not function in the way we originally hypothesized. Interestingly, the Sox9KO SSc mice actually experienced more severe disease progression compared to control mice, as skin fibrosis may actually be increased in these animals (n=6, p=0.065) and mice with SSc affecting the lungs died earlier than control mice (n=6-9,p=0.11), providing an interesting opportunity to explore this unexpected phenotype.

ESDR353 - Investigating the Contribution of Endothelial to Mesenchymal Transition (EndMT) and Vascular Sox9 to Fibrosis in Scleroderma

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING