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

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Abstract

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 m6A demethylation is involved in the regulation of MSCs differentiation potential. Exposure of MSCs to TNF-α 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 m6A 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 m6A modification suggested a novel potential therapeutic target for stem cell-mediated regenerative medicine.

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Acknowledgements

We thank Yang Caiguang at the Shanghai Institute of Materia Medica for providing MA2, Yang Yungui and Yang Ying from the Institute of Genetics, Chinese Academy of Sciences for technical support of MeRIP-qPCR. This work was 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), and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund (2017-JQPY-002).

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  1. Contributed equally to this work

Authors and Affiliations

  1. Tianjin Medical University, Tianjin, 300070, China

    Yihui Wang & Rui Wang

  2. Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China

    Yihui Wang, Rui Wang, Bin Yao, Tian Hu, Xiaoli Cui, Liuhanghang Cheng, Wei Song, Sha Huang & Xiaobing Fu

  3. School of Medicine, Nankai University, Tianjin, 300052, China

    Tian Hu

  4. Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, 100853, China

    Zhao Li, Yufan Liu, Sha Huang & Xiaobing Fu

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  1. Yihui Wang
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Correspondence to Sha Huang or Xiaobing Fu.

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Compliance and ethics The author(s) declare that they have no conflict of interest. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. All animal experiments were performed according to the protocols approved by the Ethics Committee at the General Hospital of the People’s Liberation Army and all applicable institutional and/or national guidelines for the care and use of animals were followed.

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Wang, Y., Wang, R., Yao, B. et al. TNF-α suppresses sweat gland differentiation of MSCs by reducing FTO-mediated m6A-demethylation of Nanog mRNA. Sci. China Life Sci. 63, 80–91 (2020). https://doi.org/10.1007/s11427-019-9826-7

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