Neonatal transplantation of iPSC-derived MSCs affects systemic collagen vi restoration in ullrich congenital muscular dystrophy mice

Abstract

Background & Aim Collagen VI is ubiquitously expressed extracellular matrix of skeletal muscle, which is supplemented mainly by interstitial fibroblasts. Mutations in Col6 gene cause a spectrum of COL6-related myopathies, with Ullrich congenital muscular dystrophy (UCMD) regarded at the severe end. As collagen VI is systemically defective, patients with UCMD present early-onset muscle weakness, proximal joint contracture and distal hyperextensibility. The skeletal muscle of col6a1−/− mice have a subpopulation of very small-sized myofibers, representing the characteristic pathology in which newly regenerating myofibers fail to go through the normal maturation process and remain immature and small. We hypothesized that MSC transplantation could restore collagen VI in skeletal muscles with additional therapeutic effects and performed a transplantation study using human iPSC-derived MSCs (iMSCs) on neonatal Col6a1−/−/NSG mice. Methods, Results & Conclusion We injected 5 × 106 human iMSCs with a luciferase expressing piggy-bac vector into the abdominal cavity of Col6a1−/−/NSG mice on postnatal day 2 and analyzed them at 4 weeks. Mice that received a boosting ip transplantation at 4 weeks were analyzed at 8 weeks. They were compared with non-treated Col6a1−/−/NSG mice or WT/NSG mice. Intraperitoneally transplanted iMSCs were distributed to all major organs but the brain. Both the engraftment of donor cells and resulting collagen VI restoration were confirmed at the quadriceps and diaphragm. The mice showed increased muscle weight, with enlarged diameters as well as increased total number of myofibers. Functional tests at 8 weeks showed better performance in the treated mice. Further analysis revealed that continuous muscle regeneration was maintained in the transplanted Col6a1−/−/NSG mice, with increased number of MyoD+ cells and MYH3+ myofibers compared to mice without intervention. Therefore, collagen VI supplementation by iMSC transplantation may compensate the natural course of muscle atrophic changes observed in Col6a1−/−/NSG mice by facilitating healthy muscle maturation as well as maintaining continuous regeneration. This study demonstrated the histological and functional therapeutic effects of iMSC transplantation in Col6a1−/−/NSG mice while also revealing its mechanisms. These promising results are a proof of concept for systemic MSC transplantation as a therapy for UCMD.