Volume 30, No 12, Dec 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 12, December 2020: 1063-1077   |  Open Access

ORIGINAL ARTICLES

Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration

Shen’ao Zhou^1,2 , Wei Zhang^1,2 , Gaihong Cai³ , Yingzhe Ding^4,5 , Caixia Wei¹ , Sheng Li¹ , Yu Yang^1,2 , Jie Qin¹ , Dan Liu¹ , Hao Zhang⁶ , Xiexiang Shao⁷ , Jianhua Wang⁷ , Hongye Wang¹ , Wenjun Yang¹ , Huating Wang^4,8 , She Chen^3,9 , Ping Hu^{1,2,10,11,12,13,*} , Liming Sun^1,2,10,*

¹State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
²University of Chinese Academy of Sciences, Beijing 100049, China
³National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
⁴Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories 999077 Hong Kong SAR, China
⁵Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories 999077 Hong Kong SAR, China
⁶Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
⁷Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
⁸Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories 999077 Hong Kong SAR, China
⁹Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
¹⁰Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
¹¹Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong 510005, China
¹²Bio-Research Innovation Center, Shanghai Institute of Biochemistry and Cell Biology, Suzhou, Jiangsu 215121, China
¹³Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
Correspondence: Ping Hu(hup@sibcb.ac.cn)Liming Sun(liming.sun@sibcb.ac.cn)

Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.

https://doi.org/10.1038/s41422-020-00393-6

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