摘要
An effect of inhibition of tumor necrosis factor-α(TNF-α)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-αinhibits 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-αreduced expression of FTO,which demethylated Nanog m RNA.Reduced expression of FTO increased Nanog m RNA methylation,decreased Nanog m RNA 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 cellmediated regenerative medicine.
An effect of inhibition of tumor necrosis factor-α(TNF-α) 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-α 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-αreduced expression of FTO, which demethylated Nanog m RNA. Reduced expression of FTO increased Nanog m RNA methylation, decreased Nanog m RNA 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 cellmediated regenerative medicine.
基金
funded in part by the National Natural Science Foundation of China(81571909,81721092,81701906)
the National Key R&D Program of China(2017YFC1103300)
the Beijing Natural Science Foundation(7174352)
Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund(2017-JQPY-002)
