Abstract
BackgroundDuchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder with no effective treatment that is caused by the loss of dystrophin. Human induced pluripotent stem cells (hiPSCs) offer a promising unlimited resource for cell-based therapies of muscular dystrophy. However, their clinical applications are hindered by inefficient myogenic differentiation, and moreover, the engraftment of non-transgene hiPSC-derived myogenic progenitors has not been examined in the mdx mouse model of DMD.MethodsWe investigated the muscle regenerative potential of myogenic progenitors derived from hiPSCs in mdx mice. The hiPSCs were transfected with enhanced green fluorescent protein (EGFP) vector and defined as EGFP hiPSCs. Myogenic differentiation was performed on EGFP hiPSCs with supplementary of basic fibroblast growth factor, forskolin, 6-bromoindirubin-3′-oxime as well as horse serum. EGFP hiPSCs-derived myogenic progenitors were engrafted into mdx mice via both intramuscular and intravenous injection. The restoration of dystrophin expression, the ratio of central nuclear myofibers, and the transplanted cells-derived satellite cells were accessed after intramuscular and systemic transplantation.ResultsWe report that abundant myogenic progenitors can be generated from hiPSCs after treatment with these three small molecules, with consequent terminal differentiation giving rise to mature myotubes in vitro. Upon intramuscular or systemic transplantation into mdx mice, these myogenic progenitors engrafted and contributed to human-derived myofiber regeneration in host muscles, restored dystrophin expression, ameliorated pathological lesions, and seeded the satellite cell compartment in dystrophic muscles.ConclusionsThis study demonstrates the muscle regeneration potential of myogenic progenitors derived from hiPSCs using non-transgenic induction methods. Engraftment of hiPSC-derived myogenic progenitors could be a potential future therapeutic strategy to treat DMD in a clinical setting.
Highlights
Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder with no effective treatment that is caused by the loss of dystrophin
The morphology of enhanced green fluorescent protein (EGFP) Human induced pluripotent stem cells (hiPSCs) resembled that of untransfected hiPSCs (Fig. 1a) and could be passaged as usual with normal karyotype (Fig. 1b)
To further test whether EGFP hiPSCs retained pluripotent characterization, analysis of pluripotency markers was performed and EGFP hiPSCs were induced to differentiate into three germ layers in vitro and in vivo
Summary
Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder with no effective treatment that is caused by the loss of dystrophin. Duchenne muscular dystrophy (DMD) (OMIM: 310200) is the most common form of inherited muscular dystrophy characterized by progressive skeletal muscle weakness and hypertrophy. It is a lethal X-linked recessive disease caused by mutations in dystrophin gene (DMD) (HGNC ID: 2928) [1, 2]. Satellite cells are adult stem cells capable of self-renewal and myogenic differentiation They are located between the sarcolemma and basal lamina of muscle fibers, and are distinguished by expression of paired-box transcription factor 7 (Pax7) and Pax3 [5,6,7]. Recent studies show that dystrophin deficiency leads to impairments in cell polarity, proliferation, and myogenic differentiation of satellite cells, and eventually impairs muscle regenerative processes [8, 9]
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