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Abstract

Several adult stem cell populations exhibit myogenic regenerative potential, thus representing attractive candidates for therapeutic approaches of neuromuscular diseases such as Duchenne Muscular Dystrophy (DMD). We have recently shown that systemic delivery of MuStem cells, isolated in healthy dog, generates the remodeling of muscle tissue and gives rise to striking clinical benefit in dystrophic dog. This global effect, which is observed in the clinically relevant DMD animal model, leads us to question here the molecular pathways that are impacted by MuStem cell transplantation. To address this issue, we compare the global gene expression profile between healthy, dystrophic and treated dystrophic dog muscle, four months after allogeneic MuStem cell transplantation. Disease-related deregulation is observed in the case of 282 genes related to various processes such as inflammatory response, regeneration, calcium ion binding, extracellular matrix organization, metabolism and apoptosis regulation. Importantly, we reveal the impact of MuStem cell transplantation on several molecular and cellular pathways based on a selection of 31 genes displaying signals specifically modulated by the treatment. Concomitant with a diffuse dystrophin expression, a histological remodeling and a stabilization of dystrophic dog clinical status, we show that cell delivery is associated with an up-regulation of genes reflecting a sustained enhancement of muscle regeneration. We also identify a decreased mRNA expression of a set of genes having metabolic functions associated with lipid homeostasis and energy. Interestingly, ubiquitin-mediated protein degradation is highly enhanced after MuStem cell delivery. To expand this study, we decided to investigate the skeletal muscle proteome by using quantitative proteomics with isotope-coded protein labeling. A total of 492 proteins were quantified, including 25 that were overrepresented and 46 that were underrepresented after MuStem cell transplantation. Interestingly, this study demonstrates that somatic stem cell therapy impacts on the structural integrity of the muscle fascicle by acting on fibers and its connections with the extracellular matrix. We also show that cell infusion promotes protective mechanisms against oxidative stress and favors the initial phase of muscle repair. Our results provide the first high-throughput characterization of dystrophic dog muscle and throw new light on the complex molecular/protein effects associated with muscle repair and the clinical efficacy of MuStem cell-based therapy.

PhD supervisors: Karl Rouger, Laétitia Guével

Partners: Protim, Irset INSERM UMR 1085, Rennes

Associated publications:

• Robriquet F, Lardenois A, Babarit C, Larcher T, Dubreil L, Leroux I, Zuber C, Ledevin M, Deschamps JY, Fromes Y, Cherel Y, Guevel L, Rouger K. Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation.PLoS One. 2015 May 8;10(5):e0123336. doi: 10.1371/journal.pone.0123336. eCollection 2015.
• Lardenois A, Jagot S, Lagarrigue M, Guével B, Ledevin M, Larcher T, Dubreil L, Pineau C, Rouger K, Guével L. Quantitative proteome profiling of dystrophic dog skeletal muscle reveals a stabilized muscular architecture and protection against oxidative stress after systemic delivery of MuStem cells. Proteomics. 2016 Jul;16(14):2028-42. doi: 10.1002/pmic.201600002.

2013-2016