Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production

  • EMBO J. 2021 Jun 1;40(11):e106771. doi: 10.15252/embj.2020106771.
Weiyun Wang  1 ,  Shaofang Ren  2 ,  Yunkun Lu  1 ,  Xi Chen  1 ,  Juanjuan Qu  3 ,  Xiaojie Ma  1 ,  Qian Deng  1 ,  Zhensheng Hu  1 ,  Yan Jin  1 ,  Ziyu Zhou  1 ,  Wenyan Ge  1 ,  Yibing Zhu  1 ,  Nannan Yang  4 ,  Qin Li  1 ,  Jiaqi Pu  1 ,  Guo Chen  1 ,  Cunqi Ye  1 ,  Hao Wang  4  5 ,  Xiaoyang Zhao  2 ,  Zhiqiang Liu  3 ,  Saiyong Zhu  1  6
Affiliations
  • 1. The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 2. State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 3. College of Life Science, Shanxi University, Taiyuan, China.
  • 4. Prenatal Diagnosis Center, Hangzhou Women's Hospital, Hangzhou, China.
  • 5. Department of Cell Biology and Medical Genetics, School of Medicine, Zhejiang University, Hangzhou, China.
  • 6. Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
PMID: 33909912 DOI: 10.15252/embj.2020106771
Abstract

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / Calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased Oxidative Phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

Keywords
R406; Syk; chemical reprogramming; hydrogen sulfide; metabolism.
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