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Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state

Peng Wang^1,2,3,† , Xupeng Liu^1,2,3,† , Ziyue Yao^1,2,3 , Yu Chen^1,2,3 , Lanfang Luo^1,2,3 , Kun Liang^1,2,3 , Jun-Hao Elwin Tan^4,5,6,7 , Min-Wen Jason Chua^4,5,6,7 , Yan-Jiang Benjamin Chua^4,5,6,7 , Shilin Ma^1,2,3 , Liping Zhang^1,2,3 , Wenwu Ma^1,2,3 , Shuqing Liu^1,2,3 , Wenhua Cao^1,2,3 , Luyao Guo^1,2,3 , Lu Guang^1,2,3 , Yuefan Wang^1,2,3 , He Zhao^1,2,3 , Na Ai^3,8 , Yun Li^3,8 , Chunwei Li⁹ , Ruiqi Rachel Wang^1,2 , Bin Tean Teh^6,7 , Lan Jiang⁸ , Kang Yu⁹ , Ng Shyh-Chang^1,2,3,*

¹Institute of Zoology, Chinese Academy of Sciences, Beijing, China
²Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
³University of Chinese Academy of Sciences, Beijing, China
⁴NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
⁵Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
⁶Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
⁷Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore
⁸CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
⁹Department of Clinical Nutrition, Beijing, China
^†These authors contributed equally: Peng Wang, Xupeng Liu
* Correspondence: Ng Shyh-Chang(huangsq@ioz.ac.cn)

During homeostasis and after injury, adult muscle stem cells (MuSCs) activate to mediate muscle regeneration. However, much remains unclear regarding the heterogeneous capacity of MuSCs for self-renewal and regeneration. Here, we show that Lin28a is expressed in embryonic limb bud muscle progenitors, and that a rare reserve subset of Lin28a+Pax7– skeletal MuSCs can respond to injury at adult stage by replenishing the Pax7+ MuSC pool to drive muscle regeneration. Compared with adult Pax7+ MuSCs, Lin28a+ MuSCs displayed enhanced myogenic potency in vitro and in vivo upon transplantation. The epigenome of adult Lin28a+ MuSCs showed resemblance to embryonic muscle progenitors. In addition, RNA-sequencing revealed that Lin28a+ MuSCs co-expressed higher levels of certain embryonic limb bud transcription factors, telomerase components and the p53 inhibitor Mdm4, and lower levels of myogenic differentiation markers compared to adult Pax7+ MuSCs, resulting in enhanced self-renewal and stress-response signatures. Functionally, conditional ablation and induction of Lin28a+ MuSCs in adult mice revealed that these cells are necessary and sufficient for efficient muscle regeneration. Together, our findings connect the embryonic factor Lin28a to adult stem cell self-renewal and juvenile regeneration.

https://doi.org/10.1038/s41422-023-00818-y

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