Distinct muscle regenerative capacity of human induced pluripotent stem cell-derived mesenchymal stromal cells in Ullrich congenital muscular dystrophy model mice

• Published in: Stem cell research & therapy 2024-10, Vol.15 (1), p.340-19, Article 340
• Main Authors: Yokomizo-Goto, Megumi, Takenaka-Ninagawa, Nana, Zhao, Chengzhu, Bourgeois Yoshioka, Clémence Kiho, Miki, Mayuho, Motoike, Souta, Inada, Yoshiko, Zujur, Denise, Theoputra, William, Jin, Yonghui, Toguchida, Junya, Ikeya, Makoto, Sakurai, Hidetoshi
• Format: Article
• Language: English
• Subjects: Animal experimentation; Animals; Cell Differentiation; Collagen; Collagen Type VI - genetics; Collagen Type VI - metabolism; Comparative analysis; Disease Models, Animal; Health aspects; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Insulin growth factor 2; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchymal stromal cells; Mice; Mice, Knockout; Muscle, Skeletal - metabolism; Muscles; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular Dystrophies - therapy; Muscular dystrophy; Regeneration; Scientific equipment and supplies industry; Sclerosis; Skeletal muscle regeneration; Stem cells; Type 6 collagen; Ullrich congenital muscular dystrophy
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-024-03951-6

Ullrich congenital muscular dystrophy (UCMD) is caused by a deficiency in type 6 collagen (COL6) due to mutations in COL6A1, COL6A2, or COL6A3. COL6 deficiency alters the extracellular matrix structure and biomechanical properties, leading to mitochondrial defects and impaired muscle regeneration. Therefore, mesenchymal stromal cells (MSCs) that secrete COL6 have attracted attention as potential therapeutic targets. Various tissue-derived MSCs exert therapeutic effects in various diseases. However, no reports have compared the effects of MSCs of different origins on UCMD pathology. To evaluate which MSC population has the highest therapeutic efficacy for UCMD, in vivo (transplantation of MSCs to Col6a1-KO/NSG mice) and in vitro experiments (muscle stem cell [MuSCs] co-culture with MSCs) were conducted using adipose tissue-derived MSCs, bone marrow-derived MSCs, and xeno-free-induced iPSC-derived MSCs (XF-iMSCs). In transplantation experiments on Col6a1-KO/NSG mice, the group transplanted with XF-iMSCs showed significantly enhanced muscle fiber regeneration compared to the other groups 1 week after transplantation. At 12 weeks after transplantation, only the XF-iMSCs transplantation group showed a significantly larger muscle fiber diameter than the other groups without inducing fibrosis, which was observed in the other transplantation groups. Similarly, in co-culture experiments, XF-iMSCs were found to more effectively promote the fusion and differentiation of MuSCs derived from Col6a1-KO/NSG mice than the other primary MSCs investigated in this study. Additionally, in vitro knockdown and supplementation experiments suggested that the IGF2 secreted by XF-iMSCs promoted MuSC differentiation. XF-iMSCs are promising candidates for promoting muscle regeneration while avoiding fibrosis, offering a safer and more effective therapeutic approach for UCMD than other potential therapies.