Methods and compositions for treatment of muscle disease with iPSC-induced human skeletal muscle stem cells

Abstract

Human skeletal muscle stem cells were generated from facioscapulohumeral muscular dystrophy (FSHD) and healthy control iPSC using a transgene-free skeletal muscle differentiation protocol and production of stable iMyoblasts. Analyses revealed that FSHD and healthy control iMyoblasts are embryonic-like myogenic cells that undergo myotube differentiation ex vivo by growth factor depletion and are efficiently transplantable into the tibialis anterior (TA) muscles of NSG mice, where human muscle under-goes embryonic-to-adult myosin isoform switching. The DUX4 FSHD disease gene maintains its hypomethylated disease state inFSHD iPSC and iMyoblast, and its expression is upregulated during myotube differentiation and in muscle xenografts. Consequently, these iMyoblasts accurately exhibit the molecular pathology of human muscular dystrophies and are useful for the development of drug, gene editing and stem cell therapeutics.

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