HUMAN IPSC-MOUSE CHIMERAS TO STUDY HUNTINGTON'S DISEASE PHENOTYPES

Huntington’s disease (HD) is a hereditary neurodegenerative disorder mainly characterized by striatal atrophy and degeneration of medium spiny neurons (MSNs). Although mouse models have provided a substantial amount of information about HD, they show important limitations for understanding the pathogenesis in humans. Current in vitro HD human models can recapitulate some disease phenotypes, but they are not useful for studying long-term differentiation, aging and the establishment of brain connections. Interestingly, new in vivo chimeric models using HD patient-derived induced pluripotent stem cells (iPSCs) transplanted into mice could avoid these shortcomings, by allowing cell differentiation and aging within a physiologically relevant environment. We have transplanted iPSC-derived telencephalic progenitors from healthy subjects and HD patients into the mouse developing forebrain, at both embryonic and neonatal stages. At these early ages, patterning cues present in the host developing brain act to instruct specific cell fates and play a key role in determining the migration, connectivity and functional integration of engrafted cells. Following transplantation into the mouse neonatal striatum, the vast majority of cells express CTIP2, including a subpopulation co-expressing DARPP-32, indicative of MSN identity. Furthermore, human iPSC-derived differentiated neurons sent axons towards MSN targets and were able to establish synapses, suggesting functional integration within the basal ganglia circuitry. Remarkably, transplanted cells survived up to 5 months and HD cells recapitulated human HD pathology, as evidenced by altered autophagy, mutant huntingtin aggregation and striatal degeneration. Preliminary results from in utero transplantation into the lateral ventricles of E14.5 embryos, show a wider dispersion of grafted cells compared to neonatal transplantation. Moreover, HD cells display increased branching one month after grafting. In summary, we conclude that human iPSC-mouse chimeras are a useful tool for modeling human HD in vivo.