Superoxide Dismutase 2 Promotes the Immunosuppressive Function of Mesenchymal Stem Cells at the Expense of Adipocyte Differentiation

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by pro-inflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, was decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator- activated receptor-gamma coactivator-1apha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondria mass but promoted glycolysis in an SOD2-dependent manner. Importantly, MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance immunosuppressive activity of MSCs in inflammatory microenvironment.