TNF-α-driven m6A modification disrupts the immunoregulatory function of MSCs by regulating HDAC5-dependent super-enhancers.

Mesenchymal stem cells (MSCs) are extensively utilised to treat inflammatory diseases because of their strong immunosuppressive functions. However, these functions are strongly affected by the inflammatory microenvironment in vivo, which limits the therapeutic effect of MSCs. The present study demonstrated that TNF-α impairs the immunosuppressive effect of MSCs on T-cell proliferation. Mechanistically, TNF-α treatment decreased the expression of the H3 deacetylase HDAC5 and then led to increased super-enhancer (SE) signals and increased expression of leukaemia inhibitory factor (LIF), which results in the dysfunction of MSCs' immunosuppressive effect. Intravenous infusion of MSCs overexpressing HDAC5 increased therapeutic efficacy in SKG mice with inflammatory arthritis. Notably, TNF-α downregulated HDAC5 by promoting WTAP-mediated m6A modification of HDAC5 mRNAs, which are subsequently regulated by YTHDF2 to reduce mRNA stability. Our results reveal a synergistic epigenetic regulatory mechanism between SEs and m6A modification of MSC immunosuppressive functions and provide a novel strategy to promote the clinical therapeutic potential of MSC infusion in inflammatory diseases.