Background: Multipotent mesenchymal stromal cells (MSCs) are potentially therapeutic for muscle disease because they can accumulate at the sites of injury and are immunosuppressive. MSCs are attractive candidates for cell-based strategies that target diseases with chronic inflammation, such as Duchenne muscular disease (DMD). We focused on the IL-10 based on anti-inflammatory properties and hypothesized that IL-10 could increase the typically low survival of MSCs by exerting a paracrine effect after transplantation.
Methods: We developed a continuous IL-10 expression system of MSCs using an adeno-associated virus (AAV) vector. To investigate the potential benefits of using AAV/IL-10 vector-transduced MSCs (IL-10-MSCs), we examined the cell survival rates in the skeletal muscles after intramuscular injection into mice and dogs. The systemic treatment of IL-10-MSCs derived from dental pulp (DPSCs) was comprehensive analyzed using the canine X-linked muscular dystrophy model in Japan (CXMDJ ), which has a severe phenotype similar to DMD patient.
Results: In vivo bioluminescence imaging analysis revealed higher retention of IL-10-MSCs injected into the hind-limb 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 CXMDJ model resulted in long-term engraftment of cells, slightly increased serum levels of IL-10.IL-10-hDPSCs showed remarkably reduced the expression of pro-inflammatory MCP-1 and IL-6, and upregulated stromal-derived factor-1 (SDF-1). In fact, MRI and histopathology of the hDPSC-treated CXMDJ indicated the regulation of inflammation in the muscles, but not myogenic differentiation from treated cells. hDPSC-treated CXMDJ showed improved running capability, and recovery in tetanic force with concomitantincrease in physical activity. Serum creatine kinase levels, which increased immediately after exercise, were suppressed in the IL-10-hDPSC-treated CXMDJ .
Conclusions: 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 muscleand also protected muscles with 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 beneficialIL-10 paracrine effects and may exert SDF-1.