Therapeutic potential of human myogenic reserve cells in Duchenne Muscular Dystrophy

Dr. Thomas Laumonier, University of Geneva

Abstract (lay summary see below)

Duchenne Muscular Dystrophy (DMD) is a severe and progressive neuromuscular muscle-wasting disorder that affects 1/3500 males and caused by the lack of dystrophin. Currently there is no cure to stop muscle degeneration in DMD. Muscle stem cells (MuSC)-based cell therapy holds great potential because it would allow muscle regeneration and genetic complementation for patients suffering from muscular diseases.
However, the strategy still needs to be improved as the culture conditions still impinge the regenerative capacities of amplified MuSC. We demonstrated that human myogenic reserve cells (RC) generated in vitro, are similar to quiescent MuSC with properties required for their use in cell therapy i.e. they survive, they form new myofibers and they generate Pax7+ MuSC in vivo. Moreover, as compared to other MuSC, RC hold the advantage to be generated in vitro in number compatible with therapeutic applications. However, their regenerative capacity has not yet been tested in a DMD model.
Recently, we showed that human myogenic reserve cells (RC) are heterogenous for Pax7, with a Pax7High and a Pax7Low subpopulation. We performed bulk RNA-Seq on human RC subpopulations and our results suggest that the Pax7High RC are less primed to myogenic differentiation and adopt a more stem-like state. Thus, Pax7High subpopulation may constitute an appropriate stem cell source for potential therapeutic applications in DMD. In this specific one-year project, we will assess the therapeutic potential of human RC subpopulations (Pax7High and a Pax7Low) after transplantation in immunodeficient dystrophic mice. For this purpose, we will first define strategies to isolate viable human RC subpopulations as intracellular staining for Pax7 is not compatible with in vivo injections. We will then evaluate their survival using non-invasive bioluminescent techniques and assess their function in vivo upon engraftment. The proposed project will bring new information on the regenerative capacity of human RC subpopulations in pathological DMD conditions and will open major perspectives for the possible clinical use of human RC.

Lay summary 

La dystrophie musculaire de Duchenne (DMD) est une maladie neuromusculaire grave et progressive. Il n'existe actuellement aucun remède pour guérir cette dégénérescence musculaire. La thérapie cellulaire a un grand potentiel thérapeutique car elle pourrait améliorer la régénération musculaire et restaurer l’expression de dystrophine chez les patients. Cependant, cette stratégie doit encore être améliorée car les conditions de culture réduisent dramatiquement les capacités régénératives des cellules souches musculaires (MuSC) amplifiées. Nous avons démontré que des MuSC humaines dites « reserve cells » (RC), générées in vitro, ont les propriétés requises pour leur utilisation en thérapie cellulaire. Dans ce projet, nous allons évaluer le potentiel thérapeutique de sous populations de RC humaines (Pax7High and a Pax7Low) dans des conditions pathologiques chez la souris. Ces travaux ouvriront des perspectives majeures pour une éventuelle utilisation clinique de sous populations de RC humaines.