Cell stem cell · 2026
Generation of human appetite-regulating neurons and tanycytes from pluripotent stem cells.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Abay-Nørgaard Zehra, Mueller Anika K, Hänninen Erno, Rausch Dylan, Piilgaard Louise, Trujillo Lucía Sena, Fedrizzi Lorenzo, Christensen Jens Bager, Salvador Alison, Schörling Alrik L, Mottelson Noah Wulff, Qin Qiuyu, Sampath Shruthi, Hersbach Bob, Henkenjohann Jonas, Peeters Sofie, Nikulina Viktoriia, Kruse Charlotte Høy, Li Yuan, Chinnaiya Kavitha, Placzek Marysia, Kajtez Janko, Pers Tune H, Kirkeby Agnete
Аннотация
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.