Modulation of dystrophic microenvironment to improve stem cell-mediated therapy

Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable leading to an increase in muscle damage. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Currently there is no effective therapy for Duchenne muscular dystrophy. Stem cell therapy represents a promising tool to treat the genetic diseases. On the other hand, improved therapeutics to reduce secondary features of the disease, namely necrosis, inflammation and fibrosis, will be of great importance too. A better understanding of these mechanisms could prove useful for producing new adjuvant treatments, including stem cell therapy. To date, cell-based therapies stalled by a limited impact of transplanted stem cell on the long term muscle cell replacement. The working hypothesis is that dystrophic muscle is a prohibitive environment for a proper and efficient stem cell activation and function, for myofibers survival, and for the maintenance of the rescued phenotype. In this project we aim to test the hypothesis that modifying/perturbing dystrophic microenvironment we may improve the effectiveness of stem cell-mediated therapy. Proving the role of dystrophic tissue niche on stem cell activity will improve the design of more efficient therapeutic strategies.