Department of Cell and Developmental Biology, University College London, WC1E 6DE London, UK; Stem Cell and Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Department of Cell and Developmental Biology, University College London, WC1E 6DE London, UK.
Stem Cell Reports. 2019 Mar 5;12(3):461-473. doi: 10.1016/j.stemcr.2019.01.007. Epub 2019 Feb 7.
Satellite cells are responsible for skeletal muscle regeneration. Upon activation, they proliferate as transient amplifying myoblasts, most of which fuse into regenerating myofibers. Despite their remarkable differentiation potential, these cells have limited migration capacity, which curtails clinical use for widespread forms of muscular dystrophy. Conversely, skeletal muscle perivascular cells have less myogenic potential but better migration capacity than satellite cells. Here we show that modulation of Notch and PDGF pathways, involved in developmental specification of pericytes, induces perivascular cell features in adult mouse and human satellite cell-derived myoblasts. DLL4 and PDGF-BB-treated cells express markers of perivascular cells and associate with endothelial networks while also upregulating markers of satellite cell self-renewal. Moreover, treated cells acquire trans-endothelial migration ability while remaining capable of engrafting skeletal muscle upon intramuscular transplantation. These results extend our understanding of muscle stem cell fate plasticity and provide a druggable pathway with clinical relevance for muscle cell therapy.
卫星细胞负责骨骼肌再生。在激活后，它们作为短暂扩增的成肌细胞增殖，其中大多数融合成再生的肌纤维。尽管它们具有显著的分化潜力，但这些细胞的迁移能力有限，这限制了它们在广泛形式的肌肉营养不良症中的临床应用。相比之下，骨骼肌血管周细胞的成肌潜力较低，但迁移能力比卫星细胞强。在这里，我们表明 Notch 和 PDGF 途径的调节，这些途径参与了周细胞的发育特化，可诱导成年小鼠和人卫星细胞源性成肌细胞的血管周细胞特征。DLL4 和 PDGF-BB 处理的细胞表达血管周细胞的标志物，并与内皮网络相关联，同时上调卫星细胞自我更新的标志物。此外，处理后的细胞获得了跨内皮迁移能力，同时仍然能够在肌肉内移植后植入骨骼肌。这些结果扩展了我们对肌肉干细胞命运可塑性的理解，并为肌肉细胞治疗提供了一种具有临床相关性的可用药途径。
