Expression of the lupus associated Pbx1-d isoform induces pro-inflammatory phenotypes in mesenchymal stem cells (MSCs) in a mouse model of lupus

Abstract

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease that causes chronic inflammation. It is most prevalent in women, especially in women from minority populations and is heterogeneous. In previous experiments, it has been discovered that mesenchymal stem cells (MSCs) from a lupus-prone mouse strain (Sle1a1) express a defective allele of Pbx1 (Pbx1-d), a gene that controls stemness in MSCs. Sle1a1 MSCs grow faster, differentiate quicker into osteoblasts than the B6 control, and have impaired immunosuppressive function. This data together with a significant decrease in the expression of genes associated with stemness and an increase in expression of genes associated with differentiation suggests that the Pbx1-d allele disrupts the immunoregulatory functions of MSCs. This could contribute to lupus pathogenesis. We aimed to see if Pbx1-d expression in Sle1a1 MSCs increases the expression of genes promoting inflammation and activates the innate immune system. 26 genes were selected that showed an expression fold change greater than 2 in RNA sequencing as compared to B6 control MSCs. Some of the genes belong to metabolic pathways, which we are currently validating by comparing mTOR activation, glucose metabolism and mitochondrial respiration between B6 and Sle1a1 MSCs. Preliminary results suggest a different production of inflammatory cytokines and chemokines by activated Sle1a1 MSCs. Further the supernatants of activated Sle1a1 MSCs favors Th17 polarization and impairs Treg polarization in vitro. MSC cell therapy has been considered to treat lupus. Our studies provide unique insights on how a lupus susceptibility gene impairs MSC direct functions and their interactions with T cells.