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Engraftment of human induced pluripotent stem cell-derived myogenic progenitors restores dystrophin in mice with duchenne muscular dystrophy.
Biological Research ( IF 6.7 ) Pub Date : 2020-05-19 , DOI: 10.1186/s40659-020-00288-1
Ruojie He 1, 2 , Huan Li 1, 2 , Liang Wang 1, 2 , Yaqin Li 3 , Yu Zhang 4 , Menglong Chen 4 , Yuling Zhu 1, 2 , Cheng Zhang 1, 2
Affiliation  

BACKGROUND Duchenne 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. METHODS We 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. RESULTS We 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. CONCLUSIONS This 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.

中文翻译:

植入人类诱导的多能干细胞来源的成肌祖细胞可恢复患有杜氏肌营养不良症的小鼠的肌营养不良蛋白。

背景技术杜氏肌营养不良症(DMD)是一种毁灭性的遗传性肌肉疾病,没有因肌营养不良蛋白的丧失而引起的有效治疗。人类诱导的多能干细胞(hiPSC)为肌肉营养不良的细胞疗法提供了有希望的无限资源。但是,它们的临床应用受到效率低下的成肌分化的阻碍,此外,尚未在DMD的mdx小鼠模型中检查非转基因hiPSC衍生的成肌祖细胞的植入。方法我们调查了来自hiPSC的成肌祖细胞在mdx小鼠中的肌肉再生潜能。用增强的绿色荧光蛋白(EGFP)载体转染hiPSC,并将其定义为EGFP hiPSC。补充碱性成纤维细胞生长因子,福司高林,6-溴二氮卓-3'-肟以及马血清。通过肌肉内和静脉内注射将源自EGFP hiPSCs的肌源祖细胞移植到mdx小鼠中。肌内和全身移植后,肌营养不良蛋白表达的恢复,中央核肌纤维的比例以及移植的细胞衍生的卫星细胞得以恢复。结果我们报道,在用这三种小分子处理后,hiPSC可以产生大量的成肌祖细胞,因此最终的分化产生了体外成熟的肌管。在将肌肉注射或系统移植到mdx小鼠中后,这些成肌祖细胞被植入并有助于人类源性肌纤维在宿主肌肉中的再生,恢复了肌营养不良蛋白的表达,减轻了病理病变,并在营养不良的肌肉中播种卫星细胞室。结论本研究证明了使用非转基因诱导方法从hiPSCs衍生的成肌祖细胞的肌肉再生潜力。植入hiPSC来源的成肌祖细胞可能是临床上治疗DMD的潜在未来治疗策略。
更新日期:2020-05-19
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