A human pluripotent stem cell model of FSHD-affected skeletal muscles

Facioscapulohumeral muscular dystrophy (FSHD) represents a majorunmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies.Wedeveloped a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response and cell adhesion. This cellularmodelwill be a powerful tool for studying FSHDandwill ultimately assist in the development of effective treatments for muscular dystrophies. 21 samples consisting of skeletal muscle cells differentiated in triplicate experiments from 3 normal, 3 facioscapulohumeral muscular dystrophy (FSHD1) and 1 Becker Muscular Dystrophy (BMD) hESCs.

面肩肱型肌营养不良症（Facioscapulohumeral muscular dystrophy, FSHD）以骨骼肌进行性无力与萎缩为主要特征，存在亟待解决的重大临床需求。目前学界缺乏合适的实验模型，严重阻碍了对该疾病的认知。截至目前，FSHD尚无有效治疗手段。人类胚胎干细胞（human embryonic stem cells, hESCs）有望成为可再生的骨骼肌细胞（skeletal muscle cells, SkMCs）来源，同时可替代有创的患者肌肉活检操作。本研究开发了一套可规模化的单层培养体系，可在26天内将hESCs诱导分化为成熟SkMCs，全程无需细胞分选或基因操作。本研究证实，源自FSHD1型患者hESC细胞系的SkMCs会特异性表达FSHD致病标志物双同源框4（double homeobox 4），并表现出FSHD中已报道的部分病理缺陷。与健康对照及贝克尔型肌营养不良症（Becker Muscular Dystrophy, BMD）的肌管相比，FSHD1型肌管更纤细，且会差异性调控参与细胞周期调控、氧化应激应答及细胞黏附的相关基因。该细胞模型将成为研究FSHD的有力工具，并最终助力肌营养不良症有效治疗手段的开发。本数据集包含21份骨骼肌细胞样本，均由3株健康对照、3株FSHD1型及1株贝克尔型肌营养不良症（Becker Muscular Dystrophy, BMD）hESC系经三次重复实验诱导分化获得。