Hu Daiyu, Cao Yuanqing, Cai Chenglin, Wang Guangming, Zhou Min, Peng Luying, Fan Yantao, Lai Qiong, Gao Zhengliang
Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China.
Institute 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.
Neural Regen Res. 2025 Jan 1;20(1):242-252. doi: 10.4103/NRR.NRR-D-23-00928. Epub 2024 Jan 31.
JOURNAL/nrgr/04.03/01300535-202501000-00032/figure1/v/2024-05-14T021156Z/r/image-tiff 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.
《期刊》/nrgr/04.03/01300535 - 202501000 - 00032/图1/v/2024 - 05 - 14T021156Z/图像 - 标签图像文件格式 人类大脑发育是一个复杂的过程，动物模型往往存在显著局限性。为解决这一问题，研究人员开发了多能干细胞衍生的三维结构，即类脑器官，以更准确地模拟早期人类大脑发育和疾病。为了更一致、直观地再现早期大脑发育，在本研究中，我们将前脑类器官培养技术纳入传统的无导向脑类器官培养方法。这包括在神经上皮快速扩张阶段将类器官仅在基质胶中包埋7天，然后将其从基质胶中取出进行进一步培养，从而产生了一种新型的人类脑类器官系统。这种脑类器官系统复制了早期人类大脑发育的时空特征，包括神经上皮起源、神经祖细胞的产生和维持、神经元分化和迁移以及皮质层模式的形成和构建，为发育建模和毒理学测试提供了更一致、可重复的类器官。作为概念验证，我们将重金属镉应用于这个新改进的类器官系统，以测试它是否可用于评估环境毒素的神经毒性。暴露于镉7天或14天的脑类器官在其神经发育模式中表现出严重损伤和异常，包括皮质细胞死亡爆发和过早分化。镉暴露导致神经祖细胞逐渐耗竭和类器官完整性丧失，同时伴有异位位置的代偿性细胞增殖。这个新开发的类器官平台的便利性、灵活性和可控性使其成为用于神经发育、神经学和神经毒理学研究的动物模型的强大且经济实惠的替代方案。
