Dataset Information

Generation of human hypothalamic appetite-regulating neurons and tanycytes from stem cells [BMP_data]

ABSTRACT: The balance between energy intake and expenditure is controlled by the hypothalamus, a small brain region composed of several subregionalised nuclei with high neuronal diversity which are key to controlling appetite and food intake through response to circulating hormones and metabolic. However, the cellular and functional characteristics of this highly specialised neural region has been studied mainly in animal models due to a lack of access to human experimental counterparts. Here, we fine-tuned the differentiation of human pluripotent stem cells toward hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial hypothalamus (VMH) and paraventricular nucleus (PVN), and we identified key subtype-specific progenitor markers of hypothalamic subregions. We show that the timing for addition and withdrawal of bone morphogenic protein (BMP) was essential for controlling sub-regional specification of tuberal hypothalamic progenitors along the anterior-posterior axis, balancing VMH versus ARC fates. A particular population of SHH-/NKX2.1+/RAX+/FGF10+/TBX3high posterior tuberal progenitors was identified as the source for generation of ARC-associated agouti-related peptide (AGRP) neurons and tanycytes whilst anterior tuberal SHH+/NKX2.1+/RAX+/TBX3low progenitors generated VMH phenotypes including NR5A1 neurons. Upon maturation in 2D, 3D and in vivo, ARC-patterned progenitors gave rise to multiple key appetite-regulating cell types including AGRP, prepronociceptin (PNOC), growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH) and pro-opiomelanocortin (POMC) neurons and characteristic tanycyte glial cells. Differentiated ARC cultures showed high transcriptomic similarity to the human ARC and displayed evidence of functionality by AGRP secretion and responsiveness to leptin and fibroblast growth factor 1 (FGF1). In summary, our work provides new insights into the developmental lineages underlying human hypothalamic subregional specification and enables access to highly characterized human hypothalamic ARC cultures, which will provide novel opportunities for investigating the cellular and molecular pathways triggered by obesity-associated genetic variants and appetite-regulating drugs and peptides.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296407 | GEO | 2026/05/29

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The balance between energy intake and expenditure is controlled by the hypothalamus, a small brain region composed of several subregionalised nuclei with high neuronal diversity which are key to controlling appetite and food intake through response to circulating hormones and metabolic. However, the cellular and functional characteristics of this highly specialised neural region has been studied mainly in animal models due to a lack of access to human experimental counterparts. Here, we fine-tuned the differentiation of human pluripotent stem cells toward hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial hypothalamus (VMH) and paraventricular nucleus (PVN), and we identified key subtype-specific progenitor markers of hypothalamic subregions. We show that the timing for addition and withdrawal of bone morphogenic protein (BMP) was essential for controlling sub-regional specification of tuberal hypothalamic progenitors along the anterior-posterior axis, balancing VMH versus ARC fates. A particular population of SHH-/NKX2.1+/RAX+/FGF10+/TBX3high posterior tuberal progenitors was identified as the source for generation of ARC-associated agouti-related peptide (AGRP) neurons and tanycytes whilst anterior tuberal SHH+/NKX2.1+/RAX+/TBX3low progenitors generated VMH phenotypes including NR5A1 neurons. Upon maturation in 2D, 3D and in vivo, ARC-patterned progenitors gave rise to multiple key appetite-regulating cell types including AGRP, prepronociceptin (PNOC), growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH) and pro-opiomelanocortin (POMC) neurons and characteristic tanycyte glial cells. Differentiated ARC cultures showed high transcriptomic similarity to the human ARC and displayed evidence of functionality by AGRP secretion and responsiveness to leptin and fibroblast growth factor 1 (FGF1). In summary, our work provides new insights into the developmental lineages underlying human hypothalamic subregional specification and enables access to highly characterized human hypothalamic ARC cultures, which will provide novel opportunities for investigating the cellular and molecular pathways triggered by obesity-associated genetic variants and appetite-regulating drugs and peptides.

Project description:The hypothalamus (HYP) underlies basal endocrine, physiological, and behavioral drives which inherently differ across species and sexes—ranging from growth and puberty to appetite and metabolism to social behavior. Especially in the rodent brain, these sex-differentiated functions correspond to differences in the volume, cell types, and gene expression of distinct HYP subareas. Recent studies have elucidated the transcriptional profile of single cells in the rodent ventromedial hypothalamus (VMH) and arcuate (ARC), which influence appetitive/social behaviors and growth/metabolism, respectively. However, there is a paucity of studies examining the molecular architecture of the adult human HYP, and transcriptional sex differences in the human VMH and ARC have not been characterized in single-cell or spatial contexts. Using 10x Genomics Visium and Xenium platforms, we generated a multimodal, spatially-resolved molecular atlas of human postmortem VMH and ARC from male and female adult donors. Sex-differential gene expression analysis within these regions revealed correlated autosomal expression differences, with stronger overall sex effects in the ARC. We then leveraged the single-cell-resolution of Xenium to localize sex-differential expression to cell types, finding most occur in ESR1- and KISS1-expressing neurons of the ARC. Finally, we investigated VMH and ARC gene expression in relation to genes associated with neuropsychiatric diseases, identifying a striking enrichment of genes upregulated in the male VMH for known and candidate risk genes for autism spectrum disorders. This work provides a multisample view of the human VMH and ARC in young/middle adulthood across both sexes, including data at both transcriptome-wide and single-cell resolutions, the first single-cell transcriptional atlas of molecular sex differences in the adult human VMH and ARC, and highlights potential sex-differentiated roles for VMH and ARC in neurobehavioral disorders.

Dataset Information

Generation of human hypothalamic appetite-regulating neurons and tanycytes from stem cells [BMP_data]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets