Human MuStem cells, a promising therapeutic candidate for muscular dystrophies with immunomodulatory properties
Résumé
Nowadays, allogeneic cell-based therapeutic approaches for regenerative medecine are limited by graft rejection. To counteract this major deleterious effect, immunosuppressive regimens are developed and given to patients, improving their lifespan but causing in return severe adverse effects. Over the last years, a number of adult stem cell populations including mesenchymal stem cells (MSC) and vessel-associated stem cells were described for the treatment of genetic muscle diseases. Those cells were shown to display immunomodulatory properties by acting, directly or through the secretion of soluble factors, on a large number of immune cell partners (Cossu et al., 2012; English et al., 2013). Duchenne Muscular Dystrophy (DMD) is a degenerative muscle disease characterized notably by an inflammatory component that negatively impacts on muscle regeneration activity. In this context, these original immune features attributed to stem cells could be a great advantage to improve cell engraftment and efficiency. In the laboratory, we have isolated a population of muscle-derived stem cells from healthy dog muscle tissue, called cMuStem cells, and made the proof of concept of their systemic delivery efficiency in the preclinical GRMD canine model of DMD (Rouger et al, 2011; Robriquet et al, 2015). Recently, we managed to isolate the same population from Paravertebralis muscle of 9 to 15-years old patients free of known muscle disease (hMuStem cells). It was defined as a mixed population composed of both myogenic progenitors and mesenchymal perivascular cells, and characterized by a large proliferation rate, an oligopotency as well as an in vivo myogenic regenerative potential. The aim of the study was to determine whether hMuStem cells also exhibit immunomodulatory properties. Interestingly, our preliminary data show the ability of hMuStem cells from different donors to modulate allogeneic T cell proliferation and to secrete various immunomodulatory molecules (prostaglandin-E2, indoleamin-2,3-deoxygenase-1, heme oxygenase-1 and inducible nitric-oxide synthase-1). Our data also suggest that hMuStem cells are able to interact with the complement system by inhibiting complement-mediated lysis of erythrocytes. This effect seems to be mediated by factor H, an alternative inhibitory complement pathway. Overall, our study is critical for the understanding of the interaction between MuStem cells and the immune system, as well as the design of safe and efficient allogeneic stem cell-based therapy for the treatment of muscular dystrophies.