TNF-α Driven m6A Modification Disrupts MSCs Immune Regulatory Function by Regulating HDAC5-dependent Super Enhancer [CUT&Tag]

Mesenchymal stem cells (MSCs) are widely used to treat inflammatory diseases due to their strong immunosuppressive functions. However, these functions were greatly affected by inflammatory microenvironment in vivo and therefore limited the therapeutic effect of MSCs. The present study demonstrates that TNF-α impairs immunosuppression capability of MSCs on T cells proliferation. Mechanistically, TNF-α treatment decreased the expression of H3 deacetylation eazyme HDAC5, therefore leading to the enhanced super enhancer (SE) signals and upregulated expression of leukemia inhibitory factor (LIF) in MSCs. Moreover, TNF-α downregulated HDAC5 expression through promoting WTAP-mediated m6A modification of HDAC5 mRNA, which was subsequently regulated by YTHDF2 to reduce the mRNA stability. Notably, intravenous infusion of MSCs overexpressing HDAC5 showed improved therapeutic efficacy in SKG mice with inflammatory arthritis. Our results elucidate a synergistic epigenetic regulatory mechanism between super-enhancer and m6A modification of the MSCs immunosuppressive functions, and provide a novel strategy to enhance the clinical therapeutic potential of MSC infusion in inflammatory diseases.