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

Cell Research volume 33, pages 712–726 (2023)Cite this article

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Abstract

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.

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Fig. 1: Lin28a+ stem cells contribute to satellite cells and myofibers during regeneration.
Fig. 2: Lin28a+ stem cells contribute to myofibers during regeneration.
Fig. 3: Lin28a+ cells are MuSCs with robust myogenic capacity.
Fig. 4: Lin28a+ MuSCs show enhanced myogenic potency in vitro.
Fig. 5: Epigenomic profiles show that Lin28a+ MuSCs resemble embryonic muscle progenitors.
Fig. 6: Transcriptomic profiles show that Lin28a promotes MuSC dedifferentiation.
Fig. 7: Lin28a+ MuSCs are necessary for efficient muscle regeneration.
Fig. 8: Injury-inducible Lin28a is sufficient to enhance adult muscle regeneration.

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Acknowledgements

This work was supported by the Strategic Priority Research Program of the CAS (XDA16010109), the National Key R&D Program of China (2019YFA0801700), the National Natural Science Foundation of China (91957202), and the Key Research Program of the CAS (KJZD-SW-L04). N.S.-C. is also a Howard Hughes Medical Institute (HHMI) International Scholar.

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Author notes

  1. These authors contributed equally: Peng Wang, Xupeng Liu.

Authors and Affiliations

  1. Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Peng Wang, Xupeng Liu, Ziyue Yao, Yu Chen, Lanfang Luo, Kun Liang, Shilin Ma, Liping Zhang, Wenwu Ma, Shuqing Liu, Wenhua Cao, Luyao Guo, Lu Guang, Yuefan Wang, He Zhao, Ruiqi Rachel Wang & Ng Shyh-Chang

  2. Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

    Peng Wang, Xupeng Liu, Ziyue Yao, Yu Chen, Lanfang Luo, Kun Liang, Shilin Ma, Liping Zhang, Wenwu Ma, Shuqing Liu, Wenhua Cao, Luyao Guo, Lu Guang, Yuefan Wang, He Zhao, Ruiqi Rachel Wang & Ng Shyh-Chang

  3. University of Chinese Academy of Sciences, Beijing, China

    Peng Wang, Xupeng Liu, Ziyue Yao, Yu Chen, Lanfang Luo, Kun Liang, Shilin Ma, Liping Zhang, Wenwu Ma, Shuqing Liu, Wenhua Cao, Luyao Guo, Lu Guang, Yuefan Wang, He Zhao, Na Ai, Yun Li & Ng Shyh-Chang

  4. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore

    Jun-Hao Elwin Tan, Min-Wen Jason Chua & Yan-Jiang Benjamin Chua

  5. Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore

    Jun-Hao Elwin Tan, Min-Wen Jason Chua & Yan-Jiang Benjamin Chua

  6. Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore

    Jun-Hao Elwin Tan, Min-Wen Jason Chua, Yan-Jiang Benjamin Chua & Bin Tean Teh

  7. Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore

    Jun-Hao Elwin Tan, Min-Wen Jason Chua, Yan-Jiang Benjamin Chua & Bin Tean Teh

  8. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Na Ai, Yun Li & Lan Jiang

  9. Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Chunwei Li & Kang Yu

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  1. Peng Wang
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Contributions

P.W. and X.L. designed and performed the experiments. P.W., X.L. and N.S.-C. wrote the manuscript. L. Guo helped with various experiments and mouse husbandry. J.-H.E.T., M.-W.J.C. and Y.-J.B.C. helped with HSKM and LTS cell experiments. L.L. helped with cryosection and immunofluorescence experiments. S.M. helped with Western blot experiments. W.C. helped with qRT-PCR experiments. W.M., N.A., Y.L. and L.J. helped with bioinformatics analysis. Z.Y., Y.C., K.L., L. Guang, Y.W., H.Z., R.R.W. and C.L. provided technical assistance. L.Z. and S.L. helped with mouse sampling. B.T.T., K.Y. and N.S.-C. designed and supervised the overall project.

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Correspondence to Ng Shyh-Chang.

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Wang, P., Liu, X., Yao, Z. et al. Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state. Cell Res 33, 712–726 (2023). https://doi.org/10.1038/s41422-023-00818-y

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