Study and modulation of dystrophic microenvironment to improve stem cell-mediated therapy

Duchenne muscular dystrophy (DMD) is a degenerative disease largely refractory to different therapeutic approaches. Cell-based therapies are promising methods for treating DMD but stalled by a limited impact of transplanted stem cells on the long term muscle cell replacement. Among factors that might interfere with therapeutic approaches, the dystrophic environment could represent an important determinant. Thus, a better understanding of pathogenic mechanisms affecting muscle niche should prove useful for producing new adjuvant treatments. Interleukin 6 (IL-6) is a potential candidate that might contribute to sustain a hostile degenerating environment in dystrophic muscle. In the present study we provided evidences that IL-6 can perturb muscle milieu being causally linked to the pathogenesis of muscular dystrophy. We reported that increased circulating levels of IL-6 alone are sufficient to exacerbate the dystrophic muscle phenotype, increasing muscle necrosis, inflammation and cycles of regeneration/degeneration leading to the exhaustion of the muscle stem cell pool. Moreover, IL-6 is able to enhance ROS production and to impinge the anti-oxidant response during the progression of pathology, closely approximating the severity of human disease. Otherwise, the over-expression in dystrophic muscle of a positive anabolic factor, namely mIGF-1, contributes to ameliorate muscle niche by preventing the establishment of chronic inflammation and pro-oxidant conditions. Forced expression of mIGF-1 in mdx mice is able to confer robustness to dystrophic muscle enhancing differentiation and maturation processes, also preserving muscle functionality. This results in the establishment of a qualitative environment sustaining both endogenous and transplanted stem cells, since we reported that a mesoangioblast-based stem cell therapy have a major impact on mdx/mIGF-1 muscles respect to mdx ones. Thus, the positive modulation of dystrophic muscle niche exerted by mIGF-1 has intriguing implications in the field of stem cell treatments for DMD.