Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (1): 242-252.doi: 10.4103/NRR.NRR-D-23-00928

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Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins

Daiyu Hu1, 2, 3, 4, #, Yuanqing Cao1, 2, 3, 4, #, Chenglin Cai1, 4, Guangming Wang1, 4, Min Zhou2, 3, Luying Peng4, Yantao Fan1, 2, 3, *, Qiong Lai2, 3, *, Zhengliang Gao1, 2, 3, *   

  1. 1Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China; 2Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), Shanghai University School of Medicine, Nantong, Jiangsu Province, China; 3Shanghai Engineering Research Center of Organ Repair, Shanghai University School of Medicine, Shanghai, China; 4Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
  • Online:2025-01-15 Published:1900-01-01
  • Contact: Zhengliang Gao, PhD, zhengliang_gao@tongji.edu.cn; Qiong Lai, PhD, 15079198793@163.com; Yantao Fan, PhD, fanyantao2020@gmail.com.
  • Supported by:
    This work was supported by the National Key R&D Program of China, No. 2019YFA0110300 (to ZG) and the National Natural Science Foundation of China, Nos. 81773302 (to YF), 32070862 (to ZG).

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Abstract: Human brain development is a complex process, and animal models often have significant limitations. To address this, researchers have developed pluripotent stem cell-derived three-dimensional structures, known as brain-like organoids, to more accurately model early human brain development and disease. To enable more consistent and intuitive reproduction of early brain development, in this study, we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture. This involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation, resulting in a new type of human brain organoid system. This cerebral organoid system replicated the temporospatial characteristics of early human brain development, including neuroepithelium derivation, neural progenitor cell production and maintenance, neuron differentiation and migration, and cortical layer patterning and formation, providing more consistent and reproducible organoids for developmental modeling and toxicology testing. As a proof of concept, we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins. Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns, including bursts of cortical cell death and premature differentiation. Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity, accompanied by compensatory cell proliferation at ectopic locations. The convenience, flexibility, and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental, neurological, and neurotoxicological studies.

Key words: cadmium, cell death, cell proliferation, cortical development, environmental toxins, neural progenitor cells, neurogenesis, neurotoxicology, organoids, stem cells