Generation of human appetite-regulating neurons and tanycytes from pluripotent stem cells
5 affiliations
- 1Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- 2Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- 3Department of Experimental Medical Sciences, Wallenberg Centre for Molecular Medicine (WCMM) and Lund Stem Cell Centre, Lund University, 221 84 Lund, Sweden
- 4School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK
- 5Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: [email protected]
Abstract
The arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are highly specialized hypothalamic nuclei controlling appetite and energy expenditure. Here, we demonstrate that human VMH and ARC neurons can be generated from pluripotent stem cells by fine-tuned timing and duration of bone morphogenetic protein (BMP) exposure. We identified SHH − /NKX2.1 + /FGF10 + /RAX + /TBX3 + posterior tuberal progenitors as the source of ARC cell types, including agouti-related peptide (AGRP)-, prepronociceptin (PNOC)-, growth-hormone-releasing hormone (GHRH)-, and thyrotropin-releasing hormone (TRH)-expressing neurons and β2-tanycytes. Differentiated ARC cultures showed high transcriptomic similarity to human ARC and responded to energy homeostasis-regulatory peptides including leptin, glucagon-like peptide 1 (GLP-1), ghrelin, and fibroblast growth factor 1 (FGF1). In contrast, anterior tuberal TBX3 − progenitors generated VMH-associated neurons expressing NR5A1, SOX14 , and GPR149 . Strikingly, two transcriptionally distinct pro-opiomelanocortin (POMC) subpopulations emerged from these lineages, mapping spatially to either the ARC (POMC + /TBX3 + /NR5A2 + ) or the VMH (POMC + /SOX14 + /NR5A1 + ). This model provides a cellular platform to study human hypothalamic subtype specification and pathways involved in central appetite regulation.
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BibTeX
@article{abaynorgaard2026generation,
title = {{Generation of human appetite-regulating neurons and tanycytes from pluripotent stem cells}},
author = {Zehra Abay-Nørgaard and Anika K. Mueller and Erno Hänninen and Dylan M. Belmont-Rausch and Louise Piilgaard and Lucía Sena Trujillo and L. Fedrizzi and Jens Bager Christensen and Alison Salvador and Alrik L. Schörling and Noah Mottelson and Qiuyu Qin and Shruthi Sampath and Bob Hersbach and Jonas Henkenjohann and Sofie Peeters and V.V. Nikulina and Charlotte Duhn Kruse and Yuan Li and Kavitha Chinnaiya and Marysia Placzek and Janko Kajtez and Tune H. Pers and Agnete Kirkeby},
journal = {Cell stem cell},
year = {2026},
month = jun,
doi = {10.1016/j.stem.2026.05.005},
url = {https://doi.org/10.1016/j.stem.2026.05.005},
note = {CC BY},
}
RIS
TY - JOUR
TI - Generation of human appetite-regulating neurons and tanycytes from pluripotent stem cells
AU - Zehra Abay-Nørgaard
AU - Anika K. Mueller
AU - Erno Hänninen
AU - Dylan M. Belmont-Rausch
AU - Louise Piilgaard
AU - Lucía Sena Trujillo
AU - L. Fedrizzi
AU - Jens Bager Christensen
AU - Alison Salvador
AU - Alrik L. Schörling
AU - Noah Mottelson
AU - Qiuyu Qin
AU - Shruthi Sampath
AU - Bob Hersbach
AU - Jonas Henkenjohann
AU - Sofie Peeters
AU - V.V. Nikulina
AU - Charlotte Duhn Kruse
AU - Yuan Li
AU - Kavitha Chinnaiya
AU - Marysia Placzek
AU - Janko Kajtez
AU - Tune H. Pers
AU - Agnete Kirkeby
PY - 2026
DA - 2026/06/08
JO - Cell stem cell
DO - 10.1016/j.stem.2026.05.005
UR - https://doi.org/10.1016/j.stem.2026.05.005
AB - The arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are highly specialized hypothalamic nuclei controlling appetite and energy expenditure. Here, we demonstrate that human VMH and ARC neurons can be generated from pluripotent stem cells by fine-tuned timing and duration of bone morphogenetic protein (BMP) exposure. We identified SHH − /NKX2.1 + /FGF10 + /RAX + /TBX3 + posterior tuberal progenitors as the source of ARC cell types, including agouti-related peptide (AGRP)-, prepronociceptin (PNOC)-, growth-hormone-releasing hormone (GHRH)-, and thyrotropin-releasing hormone (TRH)-expressing neurons and β2-tanycytes. Differentiated ARC cultures showed high transcriptomic similarity to human ARC and responded to energy homeostasis-regulatory peptides including leptin, glucagon-like peptide 1 (GLP-1), ghrelin, and fibroblast growth factor 1 (FGF1). In contrast, anterior tuberal TBX3 − progenitors generated VMH-associated neurons expressing NR5A1, SOX14 , and GPR149 . Strikingly, two transcriptionally distinct pro-opiomelanocortin (POMC) subpopulations emerged from these lineages, mapping spatially to either the ARC (POMC + /TBX3 + /NR5A2 + ) or the VMH (POMC + /SOX14 + /NR5A1 + ). This model provides a cellular platform to study human hypothalamic subtype specification and pathways involved in central appetite regulation.
SN - 1875-9777
SN - 1934-5909
ER -