The dysfunction of hypothalamic neurons is implicated in a number of common diseases, including obesity, hypertension, and mood and sleep disorders. To date, studies of human hypothalamic neurons have been limited due to their inaccessibility, but now (on p. 633), Florian Merkle, Kevin Eggan, Alex Schier and colleagues use two complimentary techniques to differentiate human pluripotent stem cells (hPSCs) into an array of neuropeptide-producing hypothalamic neurons. In the first approach, the researchers use a self-patterning strategy to generate hypothalamic progenitors from hPSCs (both embryonic stem cells and induced pluripotent stem cells). The subsequent maturation of these progenitors leads to the generation of neuropeptide-producing neurons that are morphologically similar to their in vivo counterparts. In the second, more readily scalable approach, the researchers direct the differentiation of hPSCs into hypothalamic progenitors by modulating pathways known to play a role in hypothalamic development. These progenitors, they report, can also be matured into neuropeptidergic neurons that adopt the gene expression profiles and morphological properties of their counterparts in the human brain. Finally, the authors demonstrate that in vitro-derived human hypothalamic neurons are able to integrate into the mouse brain and continue to express hypothalamus-specific neuropeptides. The cells generated by these approaches thus offer a promising tool for disease modelling, drug screening and therapeutic cell transplantation.
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