Abstract
BackgroundDefects 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.ResultsHere 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.ConclusionsAltogether, 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.
Highlights
Defects in α-dystroglycan (DG) glycosylation characterize a group of muscular dystrophies known as dystroglycanopathies
fukutinrelated protein (FKRP) mutations are associated with a large spectrum of dystroglycanopathies from severe forms, such as congenital muscular dystrophy and Walker–Warburg syndrome, to limb girdle muscular dystrophy type 2I (LGMD2I) [13,14,15]
Once we obtained FKRPP448L-NSG mice homozygous at all loci, the peripheral blood of these mice was analyzed by FACS, which confirmed the depletion of B, T, and NK cells in the FKRPP448L-NSG mouse model, whereas samples from control B6 and FKRPP448L mice contained all these three lymphocyte subsets (Fig. 1a)
Summary
Defects in α-dystroglycan (DG) glycosylation characterize a group of muscular dystrophies known as dystroglycanopathies. 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. 18 genes involved in the α-DG glycosylation pathway have been linked to dystroglycanopathies [10], including the fukutin-related protein (FKRP; OMIM 606596). FKRP mutations are associated with a large spectrum of dystroglycanopathies from severe forms, such as congenital muscular dystrophy and Walker–Warburg syndrome, to limb girdle muscular dystrophy type 2I (LGMD2I) [13,14,15]. As in other types of MDs, only palliative treatments are currently available for these patients
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