LAY SUMMARY

Using stem cell derived organs in a dish to study FA

Several cell and mouse models have been developed to study the pathology of FA in neurons of the dorsal root ganglia (DRG), one of the main affected tissue in FA, but none of them fully recapitulate what is observed in the disease. Moreover, while FA has traditionally been considered a neurodegenerative disease, recent evidences suggest that a potential neurodevelopmental component might contribute to the pathology. The discovery that stem cells-like cells (induced pluripotent stem cells, or iPSCs) can be obtained in the laboratory from patient skin cells is now allowing the development of better in vitro human models of diseases. New techniques have been optimized to generate from iPSC “organs” in a dish called organoids that recapitulate the 3D structure and complexity of a tissue. The first objective of this proposal is to generate DRG-like organoids from hiPSC lines derived from several FA patients. Notably, cellular population characterization will be performed at different time of the DRG like-organoid generation to unravel potential maturation defects. The second objective will be to look at the molecular signature of each cellular population associated to FA DRG-like organoids at different time point of their maturation to identify dysregulated pathways focusing in particular in pathways involved in key neurodevelopmental steps. Finally, the third objective is to validate in this patient-derived system the molecular pathways known to be dysregulated in other FA models and to investigate cellular phenotypes like mitochondrial function and oxidative stress.