Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons and are among the first neurons to degenerate in Huntington’s disease. Here (see ), Elena Cattaneo and co-workers report that human pluripotent stem (hPS) cells can be induced to differentiate into MSNs using an ontogeny-recapitulating protocol. The researchers induce ventral telencephalic specification of hPS cells in feeder-free adherent cultures using BMP/TGFβ inhibition followed by sonic hedgehog/WNT pathway modulation. They then induce terminal differentiation of the telencephalic progenitors in the presence of brain-derived neurotrophic factor, thereby generating MSNs that express DARPP-32 and other striatal markers. These MSNs carry dopamine and adenosine receptors, elicit a typical firing pattern, and show dopamine-dependent neuromodulation and synaptic integration ability in vivo. Finally, when transplanted into the striatum of a rat model for Huntington’s disease, hPS cell-derived neurons survive and correct motor deficits. This ontogeny-recapitulating method provides a platform for human neurodevelopmental biology studies, suggest the researchers, and could be used to develop a Huntington’s disease model for drug screening.
