TNF-α suppresses sweat gland differentiation of MSCs by reducing FTO-mediated m6A-demethylation of Nanog mRNA

An effect of inhibition of tumor necrosis factor-alpha (TNF-alpha) on differentiation of mesenchymal stromal cells (MSCs) has been demonstrated, but the exact mechanisms that govern MSCs differentiation remain to be further elucidated. Here, we show that TNF-alpha inhibits the differentiation of MSCs to sweat glands in a specific sweat gland-inducing environment, accompanied with reduced expression of Nanog, a core pluripotency factor. We elucidated that fat mass and obesity-associated protein (FTO)-mediated m(6)A demethylation is involved in the regulation of MSCs differentiation potential. Exposure of MSCs to TNF-alpha reduced expression of FTO, which demethylated Nanog mRNA. Reduced expression of FTO increased Nanog mRNA methylation, decreased Nanog mRNA and protein expression, and significantly inhibited MSCs capacity for differentiation to sweat gland cells. Our finding is the first to elucidate the functional importance of m(6)A modification in MSCs, providing new insights that the microenvironment can regulate the multipotency of MSCs at the post-transcriptional level. Moreover, to maintain differentiation capacity of MSCs by regulating m(6)A modification suggested a novel potential therapeutic target for stem cell-mediated regenerative medicine.