Stem Cells & Development, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du Dr. Roux, Paris, France.
CNRS UMR 3738, Institut Pasteur, Paris, France.
PLoS Genet. 2020 Oct 30;16(10):e1009022. doi: 10.1371/journal.pgen.1009022. eCollection 2020 Oct.
Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.
成体骨骼肌在维持内稳态的过程中，以及在受伤后通过肌肉干细胞（MuSCs）进行再生。基于其解剖位置，MuSCs 的自我更新、分化和再生特性存在异质性。尽管源自眼外肌（EOM）的 MuSCs 比源自肢体肌肉的 MuSCs 具有更高的再生能力，但支配这些差异的分子决定因素仍未确定。在这里，我们表明 EOM 和肢体 MuSCs 具有与位置特异性基因增强子相关的不同 DNA 甲基化特征，并且 EOM 转录组在移植到肢体肌肉环境后会重新编程。值得注意的是，EOM MuSCs 在植入和在宿主肌肉中自我更新后表达了宿主部位特异性的位置 Hox 代码。然而，约 10%的 EOM 特异性基因表现出植入抵抗表达，这表明 EOM MuSCs 更高植入潜力的内在分子决定因素。我们的研究结果强调了不同 MuSC 群体的分子多样性，并从分子上定义了它们对微环境线索的可塑性。这些发现为设计旨在提高 MuSCs 在再生医学背景下的功能能力的策略提供了思路。
