Abstract
Objectives Mesenchymal stromal cells (MSCs) are non-hematopoietic multipotent cells with immunomodulatory, proangiogenic, and antifibrotic properties.[1] The 3 pathogenic axes in systemic sclerosis (SSc) are autoimmunity, vasculopathy, and fibrosis.[2] Considering that donor characteristics impact MSCs’ functional properties,[3] we hypothesized that adipose-derived MSCs in SSc are dysfunctional. We aimed to characterize MSC’s phenotype from healthy donors and SSc patients.
Methods MSCs were isolated from adipose tissue contained in 2 4 mm forearm punch biopsies performed on 8 SSc patients and 8 age- and sex-matched healthy controls (Ctrl). MSCs were characterized according to the International Society for Cell and Gene Therapy (ISCT) minimal criteria. Bulk RNA sequencing was done and differentially expressed genes (DEGs) were defined as a fold change >2 or <−2, and a Benjamini-Hochberg adjusted p-value <0.05. Unsupervised hierarchical clustering and gene set enrichment analysis (GSEA) were conducted to identify enriched biological processes and signaling pathways.
Results SSc and Ctrl MSCs met ISCT criteria (ie, adhered to plastic, differentiated into 3 lineages, and exhibited specific surface markers). Compared to Ctrl, SSc MSCs had 151 upregulated and 16 downregulated genes (Figure 1A). GSEA documented the enrichment of profibrotic and senescence pathways in SSc MSCs (Figure 1B-C) which depicted a myofibroblast-like phenotype, characterized by increased ACTA2 expression.
Conclusion SSc MSCs have a distinct transcriptomic profile with enrichment of profibrotic and senescence pathways which may contribute to disease pathogenesis. Future studies will explore the effects of MSC modulation on mitigating SSc severity.
References [1.] Farge D. Autoimmun Rev 2021;20:102755. [2.] Denton CP. Lancet 2017;390:1685-99. [3.] Kizilay Mancini O. Stem Cell Res Ther 2015;8:140.
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