Enhanced cell survival and therapeutic benefits of IL-10-expressing multipotent mesenchymal stromal cells for muscular dystrophy

• Published in: Stem cell research & therapy 2021-02, Vol.12 (1), p.105-105, Article 105
• Main Authors: Nitahara-Kasahara, Yuko, Kuraoka, Mutsuki, Oda, Yuki, Hayashita-Kinoh, Hiromi, Takeda, Shin'ichi, Okada, Takashi
• Format: Article
• Language: English
• Subjects: Anti-inflammatory agents; Antibodies; Antigens; Automation; Bioluminescence; Bone marrow; Canine teeth; Cell differentiation; Cell survival; Creatine; Creatine kinase; Cytokines; Dental pulp; Dental pulp stromal cells; DMD; Dogs; Engraftment; Exercise; Experiments; Genetic vectors; Health aspects; IL-10; Immunosuppressive agents; Inflammation; Injection; Interleukin 10; Laboratory animals; Magnetic resonance imaging; Mesenchymal stem cells; Mesenchymal stromal cells; Mesenchyme; Monocyte chemoattractant protein 1; Muscles; Muscular diseases; Muscular dystrophy; Nitrogen; Paracrine signalling; Phenotypes; Physical activity; SDF-1 protein; Serum levels; Skeletal muscle; Stem cells; Stromal cells; Transplantation; Tumor necrosis factor-TNF
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-021-02168-1

Multipotent mesenchymal stromal cells (MSCs) are potentially therapeutic for muscle disease because they can accumulate at the sites of injury and act as immunosuppressants. MSCs are attractive candidates for cell-based strategies that target diseases with chronic inflammation, such as Duchenne muscular disease (DMD). We focused on the anti-inflammatory properties of IL-10 and hypothesized that IL-10 could increase the typically low survival of MSCs by exerting a paracrine effect after transplantation. We developed a continuous IL-10 expression system of MSCs using an adeno-associated virus (AAV) vector. To investigate the potential benefits of IL-10 expressing AAV vector-transduced MSCs (IL-10-MSCs), we examined the cell survival rates in the skeletal muscles after intramuscular injection into mice and dogs. Systemic treatment with IL-10-MSCs derived from dental pulp (DPSCs) was comprehensively analyzed using the canine X-linked muscular dystrophy model in Japan (CXMD ), which has a severe phenotype similar to that of DMD patients. In vivo bioluminescence imaging analysis revealed higher retention of IL-10-MSCs injected into the hindlimb muscle of mice. In the muscles of dogs, myofiber-like tissue was formed after the stable engraftment of IL-10-MSCs. Repeated systemic administration of IL-10-DPSCs into the CXMD model resulted in long-term engraftment of cells and slightly increased the serum levels of IL-10. IL-10-hDPSCs showed significantly reduced expression of pro-inflammatory MCP-1 and upregulation of stromal-derived factor-1 (SDF-1). MRI and histopathology of the hDPSC-treated CXMD indicated the regulation of inflammation in the muscles, but not myogenic differentiation from treated cells. hDPSC-treated CXMD showed improved running capability and recovery in tetanic force with concomitant increase in physical activity. Serum creatine kinase levels, which increased immediately after exercise, were suppressed in IL-10-hDPSC-treated CXMD . In case of local injection, IL-10-MSCs could maintain the long-term engraftment status and facilitate associated tissue repair. In case of repeated systemic administration, IL-10-MSCs facilitated the long-term retention of the cells in the skeletal muscle and also protected muscles from physical damage-induced injury, which improved muscle dysfunction in DMD. We can conclude that the local and systemic administration of IL-10-producing MSCs offers potential benefits for DMD therapy through the beneficial paracrine ef