The Francis Crick Institute, London, UK.
Department of Cell and Developmental Biology, University College London, London, UK.
EMBO Mol Med. 2022 Oct 10;14(10):e14526. doi: 10.15252/emmm.202114526. Epub 2022 Sep 26.
Muscle satellite stem cells (MuSCs) are responsible for skeletal muscle growth and regeneration. Despite their differentiation potential, human MuSCs have limited in vitro expansion and in vivo migration capacity, limiting their use in cell therapies for diseases affecting multiple skeletal muscles. Several protocols have been developed to derive MuSC-like progenitors from human induced pluripotent stem (iPS) cells (hiPSCs) to establish a source of myogenic cells with controllable proliferation and differentiation. However, current hiPSC myogenic derivatives also suffer from limitations of cell migration, ultimately delaying their clinical translation. Here we use a multi-disciplinary approach including bioinformatics and tissue engineering to show that DLL4 and PDGF-BB improve migration of hiPSC-derived myogenic progenitors. Transcriptomic analyses demonstrate that this property is conserved across species and multiple hiPSC lines, consistent with results from single cell motility profiling. Treated cells showed enhanced trans-endothelial migration in transwell assays. Finally, increased motility was detected in a novel humanised assay to study cell migration using 3D artificial muscles, harnessing advanced tissue modelling to move hiPSCs closer to future muscle gene and cell therapies.
肌卫星干细胞 (MuSCs) 负责骨骼肌的生长和再生。尽管具有分化潜力,但人类 MuSCs 在体外扩增和体内迁移能力有限,限制了它们在针对影响多种骨骼肌的疾病的细胞治疗中的应用。已经开发了几种方案来从人类诱导多能干细胞 (hiPSC) 中衍生出 MuSC 样祖细胞,以建立具有可控增殖和分化能力的成肌细胞来源。然而,目前的 hiPSC 成肌细胞衍生物也受到细胞迁移能力的限制,最终延迟了它们的临床转化。在这里,我们使用包括生物信息学和组织工程在内的多学科方法来证明 DLL4 和 PDGF-BB 可改善 hiPSC 衍生的成肌祖细胞的迁移能力。转录组分析表明,这种特性在不同物种和多种 hiPSC 系中是保守的,与单细胞迁移分析的结果一致。在 Transwell 测定中,处理过的细胞表现出增强的跨内皮迁移。最后,在使用 3D 人造肌肉研究细胞迁移的新型人源化测定中检测到了迁移能力的提高,利用先进的组织建模使 hiPSC 更接近未来的肌肉基因和细胞治疗。