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Generation of human pineal gland organoids with melatonin production for disease modeling

ABSTRACT: The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290048 | GEO | 2026/01/20

REPOSITORIES: GEO

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Project description:The zebrafish pineal gland (epiphysis) is an autonomous clock organ. In addition to being a site of melatonin production, it contains photoreceptor cells and functions as a circadian clock pace maker, making zebrafish a useful model system to study the developmental control of expression of genes associated with melatonin synthesis and photodetection, and the circadian clock. Here we have used DNA microarray technology to study the zebrafish pineal transcriptome. Analysis of gene expression at five different developmental stages (three embryonic and two adult) has revealed a highly dynamic transcriptional profile, revealing many genes that are highly expressed in the pineal gland. Statistical analysis of the data based on Gene Ontology (GO) annotation indicates that many transcription factors and cell cycle genes are highly expressed during embryonic stages, whereas genes dedicated to visual system signal transduction are preferentially expressed in the adult. Furthermore, several genes were identified that exhibit day/night differences in expression. Our data provide a rich source of candidate genes for distinct functions at different stages of pineal gland development. Experiment Overall Design: Adults and embryos were kept under a 14-hr-light/10-hr-dark cycle. Pineal glands were isolated manually, guided by GFP fluorescence, from embryonic (3d, 5d, and 10d) and adult (3 month and 1-2 yr) transgenic zebrafish in which expression of the GFP gene is driven by the pineal-specific aanat2 promoter. For comparison, brain tissue from which the pineal gland and eyes had been removed was also collected (referred to as “brain”). Altogether, we collected 20 types of samples: five time points (3d, 5d, 10d, 3 mo, and 1-2 yr), two organs (pineal gland and brain), and two sampling times (day and night). For each type of sample, tissue was obtained and processed three to five times. Total RNA was prepared from each sample using the RNeasy Lipid Tissue Mini Kit (Qiagen) and biotin-labeled cDNA was generated using the Ovation Biotin system kit (NeuGen). The Affymetrix GeneChip® Zebrafish Genome Array was hybridized and processed using the standard Affymetrix protocol.

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Generation of human pineal gland organoids with melatonin production for disease modeling

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