Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a ‘self-patterning’ strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases.
Author contributions
F.T.M., A.F.S. and K.E. conceived the project. F.T.M. performed all experiments and wrote the manuscript. A.F.S. and K.E. assisted with experimental design, data interpretation and manuscript preparation. T.W., Y.S., A.M. and L.S. provided access to protocols, gave advice on hypothalamic differentiation and provided comments on the manuscript.
Funding
This work was supported by grants from the Jane Coffin Childs Memorial Fund for Cancer Research, the Harvard Stem Cell Institute, the Howard Hughes Medical Institute and the National Institutes of Health [1R21NS071598, 5K99NS083713]. Deposited in PMC for release after 12 months.
