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.

中文翻译：

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移植后肌肉干细胞的转录组和表观基因组多样性和可塑性

成年骨骼肌在稳态过程中得以维持，并在受到肌肉干细胞（MuSCs）损伤后得以再生。据报道，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MuSC具有比源自肢体肌肉的MuSC更高的再生能力，但控制这些差异的分子决定因素仍然不确定。在这里，我们显示EOM和肢体MuSC具有与位置特定基因的增强子相关的不同的DNA甲基化特征，并且在移植到肢体肌肉环境后重新编程了EOM转录组。值得注意的是，EOM MuSCs在宿主肌肉内植入和自我更新后表达了宿主位点的特定位置Hox码。然而，约10％的EOM特异性基因显示出抗移植性表达，这表明EOM MuSCs具有更高的植入潜能的细胞内在分子决定因素。我们的结果强调了不同MuSC种群的分子多样性，并在分子上定义了它们对微环境线索的可塑性。这些发现为再生医学背景下旨在提高MuSCs功能能力的策略提供了见识。