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

Abstract

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 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 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 comprehensively analyzed using the canine X-linked muscular dystrophy model in Japan (CXMDJ), which has a severe phenotype similar to DMD patients. 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 expression of pro-inflammatory MCP-1, 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 concomitant increase 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 muscle and 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 beneficial IL-10 paracrine effects involving SDF-1.