Intraosseous transplant of dystrophin expressing chimeric (DEC) cells improves skeletal muscle function in mdx mouse model of Duchenne muscular dystrophy.

Introduction: We previously reported that systemic delivery of dystrophin expressing chimeric (DEC) cells of normal (wt) and dystrophin-deficient (mdx) myoblast (MB) or mesenchymal stem cell (MSC) origin restored dystrophin expression and improved cardiac function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Aim: This study evaluated the effect of intraosseous delivery of murine DEC lines of MB (MBwt/MBmdx) and MSC (MBwt/MSCmdx) origin on function of gastrocnemius muscle (GM). Material and methods: DEC lines created by ex vivo fusion were tested in the mdx mouse model of DMD: Group 1 - vehicle (control), Group 2 - non-fused 0.25 × 106 MBwt and 0.25 × 106 MSCmdx (control), Group 3 - fused 0.5 × 106 MBwt/MBmdx DEC and Group 4 - fused 0.5 × 106 MBwt/MSCmdx DEC. In situ and in vitro muscle force tests assessed GM function at 90 days post-transplant. Results: Application of MBwt/MSCmdx and MBwt/MBmdx DEC significantly improved the fatigue ratio of GM compared to vehicle-injected controls detected by in vivo muscle force tests (0.567 ±0.116, p = 0.045 and 0.489 ±0.087, p < 0.05, respectively). MBwt/MSCmdx DEC recipients presented enhanced maximum force at tetanus (0.145 ±0.040 g/mg, p < 0.05); furthermore, recipients of MBwt/MBmdx DEC showed a significant increase in the maximum force generation rate compared to vehicle controls (4.447 ±1.090 g/s/mg, p < 0.05). The ex vivo GM force testing in MBwt/MSCmdx DEC recipients detected increased average GM force compared to vehicle and non-fused controls. Conclusions: Systemic-intraosseous administration of MBwt/MBmdx and MBwt/MSCmdx DEC therapy combining the myogenic and immunomodulatory properties of MB and MSC significantly improved skeletal muscle (GM) function of force and resistance to fatigue in an mdx mouse model of DMD. [ABSTRACT FROM AUTHOR]