A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy‐Affected Skeletal Muscles

Stem Cells Translational Medicine

Kian Leong Lee¹  Jia Li¹  Lorenz Poellinger¹  Henry Yang¹  Daniel G. Miller²  Lisa M. Petek²  Davide Gabellini³  Giulia Ferri³  Heather Main⁴  Uli Schmidt⁴  Robert McKernan⁴  Devaki Kher⁴  Biljana Dumevska⁴  Alejandro Hidalgo⁴  Leslie Caron⁴ 

[1] Cancer Science Institute of Singapore, National University of Singapore, Singapore;Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA;Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy;Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia;

关键词: Embryonic stem cells;    Muscular dystrophy;    Pluripotent stem cells;    Skeletal muscle;    Induced pluripotent stem cells;   

DOI  :  10.5966/sctm.2015-0224

来源: DOAJ

【 摘 要 】

Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet 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. We developed 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 cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. Significance This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease‐specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell‐based cellular model for a muscular dystrophy that is suitable for high‐throughput screening and drug development.

【 授权许可】

Unknown