Systemic Supplementation of Collagen VI by Neonatal Transplantation of iPSC-Derived MSCs Improves Histological Phenotype and Function of Col6-Deficient Model Mice.

Aya Harada,Nana Takenaka-Ninagawa,Akito Tanaka,Makoto Ikeya,Hidetoshi Sakurai,Atsuya Kato,Megumi Goto,Satoru Noguchi

doi:10.3389/fcell.2021.790341

Aya Harada, Nana Takenaka-Ninagawa + Show 6 more

Open Access

https://doi.org/10.3389/fcell.2021.790341

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Abstract

Collagen VI is distributed in the interstitium and is secreted mainly by mesenchymal stromal cells (MSCs) in skeletal muscle. Mutations in COL6A1-3 genes cause a spectrum of COL6-related myopathies. In this study, we performed a systemic transplantation study of human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) into neonatal immunodeficient COL6-related myopathy model (Col6a1 KO /NSG) mice to validate the therapeutic potential. Engraftment of the donor cells and the resulting rescued collagen VI were observed at the quadriceps and diaphragm after intraperitoneal iMSC transplantation. Transplanted mice showed improvement in pathophysiological characteristics compared with untreated Col6a1 KO /NSG mice. In detail, higher muscle regeneration in the transplanted mice resulted in increased muscle weight and enlarged myofibers. Eight-week-old mice showed increased muscle force and performed better in the grip and rotarod tests. Overall, these findings support the concept that systemic iMSC transplantation can be a therapeutic option for COL6-related myopathies.

Highlights

Ullrich congenital muscular dystrophy (UCMD), which is regarded as the severe end of COL6related myopathy, is a life-threatening muscular and connective tissue disorder, characterized by early-onset muscle weakness with multiple joint contractures and distal joint hyperlaxity (Bönnemann, 2011)
We demonstrated that the intraperitoneal (i.p.) injection of iMSCs contributed to the expression of collagen VI among skeletal muscles and increased the size and number of myofibers by upregulating muscle regeneration
We evaluated the potential of human iMSCs to deliver collagen VI to the skeletal muscles in Col6a1KO/NSG mice after neonatal i. p. injection

Summary

Introduction

Ullrich congenital muscular dystrophy (UCMD), which is regarded as the severe end of COL6related myopathy, is a life-threatening muscular and connective tissue disorder, characterized by early-onset muscle weakness with multiple joint contractures and distal joint hyperlaxity (Bönnemann, 2011). Col6a1GT/GT mice were generated by knocking in a point mutation in exon 9 in Col6a1 gene (Noguchi et al, 2017). The resulting miss-splicing after exon 9 causes a marked reduction in normal Col6a1 mRNA expression and a premature stop codon, resulting in Col6a1 knockout and the mice having no collagen VI protein in all tissues (Noguchi et al, 2017). We refer to Col6a1GT/GT mice as Col6a1KO mice in this manuscript Both conventional Col6a1−/− mice and Col6a1KO mice are phenotypically similar, but Col6a1KO mice have a smaller body weight (BW) than WT mice (Bonaldo et al., 1998; Noguchi et al, 2017). Histological phenotypes, such as variations in myofiber size and an increased number of myofibers with central nuclei, are observed in both

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