Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Stem Cell. 2021 Sep 2;28(9):1657-1670.e10. doi: 10.1016/j.stem.2021.04.006. Epub 2021 May 6.
Human brain organoids represent remarkable platforms for recapitulating features of human brain development and diseases. Existing organoid models do not resolve fine brain subregions, such as different nuclei in the hypothalamus. We report the generation of arcuate organoids (ARCOs) from human induced pluripotent stem cells (iPSCs) to model the development of the human hypothalamic arcuate nucleus. Single-cell RNA sequencing of ARCOs revealed significant molecular heterogeneity underlying different arcuate cell types, and machine learning-aided analysis based on the neonatal human hypothalamus single-nucleus transcriptome further showed a human arcuate nucleus molecular signature. We also explored ARCOs generated from Prader-Willi syndrome (PWS) patient iPSCs. These organoids exhibit aberrant differentiation and transcriptomic dysregulation similar to postnatal hypothalamus of PWS patients, indicative of cellular differentiation deficits and exacerbated inflammatory responses. Thus, patient iPSC-derived ARCOs represent a promising experimental model for investigating nucleus-specific features and disease-relevant mechanisms during early human arcuate development.
人脑类器官代表了重现人类大脑发育和疾病特征的卓越平台。现有的类器官模型无法解析精细的脑区，如下丘脑的不同核团。我们报告了从人类诱导多能干细胞（iPSC）中生成弓状类器官（ARCOs），以模拟人类下丘脑弓状核的发育。对 ARCOs 的单细胞 RNA 测序揭示了不同弓状细胞类型背后的显著分子异质性，基于新生儿人类下丘脑单核转录组的机器学习辅助分析进一步显示了人类弓状核的分子特征。我们还探索了来自普拉德-威利综合征（PWS）患者 iPSC 生成的 ARCOs。这些类器官表现出异常的分化和转录组失调，类似于 PWS 患者的产后下丘脑，表明细胞分化缺陷和炎症反应加剧。因此，源自患者 iPSC 的 ARCOs 代表了一种有前途的实验模型，可用于研究早期人类弓状发育过程中的核特异性特征和与疾病相关的机制。
