Generation of Hypothalamic Arcuate Organoids from Human Induced Pluripotent Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 May 7

PMID 33961804

Citations 69

Authors

Wei-Kai Huang

Samuel Zheng Hao Wong

Sarshan R Pather

Phuong T T Nguyen

Feng Zhang

Daniel Y Zhang

Zhijian Zhang

Lu Lu

Wanqi Fang

Luyun Chen

Analiese Fernandes

Yijing Su

Hongjun Song

Guo-Li Ming

Affiliations

Soon will be listed here.

Abstract

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.

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