<br>Lin28a 将成体肌肉干细胞的子集维持在胚胎样状态,Cell Research

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Lin28a 将成体肌肉干细胞的子集维持在胚胎样状态
Cell Research ( IF 28.1 ) Pub Date : 2023-05-15 , DOI: 10.1038/s41422-023-00818-y
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 Li ₉ , Ruiqi Rachel Wang _{1,

2} , Bin Tean Teh _{6,

7} , Lan Jiang ₈ , Kang Yu ₉ , Ng Shyh-Chang _{1,

2,

3}

Affiliation

Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
Institute of Molecular and Cell Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore.
Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore, Singapore.
Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore.
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

在稳态期间和受伤后，成体肌肉干细胞（MuSC）激活以介导肌肉再生。然而，关于 MuSC 自我更新和再生的异质能力仍不清楚。在这里，我们表明 Lin28a 在胚胎肢芽肌肉祖细胞中表达，并且 Lin28a ⁺ Pax7 的罕见储备子集^-骨骼 MuSC 可以通过补充 Pax7 ⁺ MuSC 池来响应成年阶段的损伤，以驱动肌肉再生。与成人 Pax7 ⁺ MuSC 相比，Lin28a ⁺ MuSC 在移植后在体外和体内表现出增强的生肌效力。成年 Lin28a ⁺ MuSC 的表观基因组与胚胎肌肉祖细胞相似。此外，RNA测序显示，与成人Pax7 ⁺ MuSCs相比，Lin28a ⁺ MuSCs共同表达较高水平的某些胚胎肢芽转录因子、端粒酶成分和p53抑制剂Mdm4，以及较低水平的肌源性分化标记物，从而增强了自我能力。 -更新和压力反应签名。从功能上讲，成年小鼠中 Lin28a ⁺ MuSC 的条件消融和诱导表明，这些细胞对于有效的肌肉再生是必要且充分的。总之，我们的研究结果将胚胎因子 Lin28a 与成体干细胞自我更新和幼体再生联系起来。

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

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.

更新日期：2023-05-16

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