Defects in α-dystroglycan (DG) glycosylation characterize a group of muscular dystrophies known as dystroglycanopathies. One of the key effectors in the α-DG glycosylation pathway is the glycosyltransferase fukutin-related protein (FKRP). Mutations in FKRP lead to a large spectrum of muscular dystrophies, including limb girdle muscular dystrophy 2I (LGMD2I). It remains unknown whether stem cell transplantation can promote muscle regeneration and ameliorate the muscle wasting phenotype associated with FKRP mutations. Here we transplanted murine and human pluripotent stem cell-derived myogenic progenitors into a novel immunodeficient FKRP-mutant mouse model by intra-muscular injection. Upon both mouse and human cell transplantation, we observe the presence of donor-derived myofibers even in absence of pre-injury, and the rescue of α-DG functional glycosylation, as shown by IIH6 immunoreactivity. The presence of donor-derived cells expressing Pax7 under the basal lamina is indicative of satellite cell engraftment, and therefore, long-term repopulation potential. Functional assays performed in the mouse-to-mouse cohort revealed enhanced specific force in transplanted muscles compared to PBS-injected controls. Altogether, our data demonstrate for the first time the suitability of a cell-based therapeutic approach to improve the muscle phenotype of dystrophic FKRP-mutant mice.

中文翻译：

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多能干细胞衍生的肌源性祖细胞在新型免疫缺陷小鼠肢带型肌营养不良症 2I 模型中的有效植入。


α-肌营养不良聚糖 (DG) 糖基化缺陷是一组称为营养不良聚糖病的肌营养不良症的特征。 α-DG 糖基化途径中的关键效应子之一是糖基转移酶 fukutin 相关蛋白 (FKRP)。 FKRP 突变会导致多种肌营养不良症，包括肢带型肌营养不良症 2I (LGMD2I)。目前尚不清楚干细胞移植是否可以促进肌肉再生并改善与 FKRP 突变相关的肌肉消耗表型。在这里，我们通过肌内注射将小鼠和人类多能干细胞衍生的肌源性祖细胞移植到新型免疫缺陷 FKRP 突变小鼠模型中。在小鼠和人类细胞移植中，即使没有损伤前，我们也观察到供体来源的肌纤维的存在，以及 α-DG 功能性糖基化的恢复，如 IIH6 免疫反应性所示。基底层下表达 Pax7 的供体来源细胞的存在表明卫星细胞植入，因此具有长期再增殖潜力。在小鼠对小鼠队列中进行的功能测定显示，与注射 PBS 的对照组相比，移植肌肉的比力有所增强。总而言之，我们的数据首次证明基于细胞的治疗方法适用于改善营养不良的 FKRP 突变小鼠的肌肉表型。