2. Academic Validation
  3. Generation of human pineal gland organoids with melatonin production for disease modeling

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

  • Cell Stem Cell. 2026 Jan 8;33(1):91-107.e9. doi: 10.1016/j.stem.2025.12.004.
Ferdi Ridvan Kiral 1,  Woo Sub Yang 1,  Onur Iyilikci 2,  Xiaona Lu 3,  Jonghun Kim 1,  Mu Seog Choe 1,  Cynthia Lo 1,  Mei Zhong 4,  Kun-Yong Kim 3,  Yong-Hui Jiang 5,  In-Hyun Park 6
Affiliations

Affiliations

  • 1 Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
  • 2 Department of Psychology, Koc University, Istanbul 34450, Türkiye.
  • 3 Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
  • 4 Department of Cell Biology, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
  • 5 Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
  • 6 Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].
PMID: 41475351 DOI: 10.1016/j.stem.2025.12.004
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.

Keywords

Angelman syndrome; cell therapy; development; melatonin; neurodevelopmental disorders; organoids; pineal gland; sleep; stem cells.

Figures
Products