Brain organoids have emerged as a novel model system for neural development, neurodegenerative diseases, and human-based drug screening. However, the heterogeneous nature and immature neuronal development of brain organoids generated from pluripotent stem cells pose challenges. Moreover, there are no previous reports of a three-dimensional (3D) hypoxic brain injury model generated from neural stem cells. Here, we generated self-organized 3D human neural organoids from adult dermal fibroblast-derived neural stem cells. Radial glial cells in these human neural organoids exhibited characteristics of the human cerebral cortex trend, including an inner (ventricular zone) and an outer layer (early and late cortical plate zones). These data suggest that neural organoids reflect the distinctive radial organization of the human cerebral cortex and allow for the study of neuronal proliferation and maturation. To utilize this 3D model, we subjected our neural organoids to hypoxic injury. We investigated neuronal damage and regeneration after hypoxic injury and reoxygenation. Interestingly, after hypoxic injury, reoxygenation restored neuronal cell proliferation but not neuronal maturation. This study suggests that human neural organoids generated from neural stem cells provide new opportunities for the development of drug screening platforms and personalized modeling of neurodegenerative diseases, including hypoxic brain injury.

中文翻译：

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通过 3D 人体神经类器官模拟缺氧脑损伤

脑类器官已成为神经发育、神经退行性疾病和基于人类的药物筛选的新型模型系统。然而，多能干细胞产生的脑类器官的异质性和未成熟的神经元发育带来了挑战。此外，之前没有关于由神经干细胞生成的三维 (3D) 缺氧脑损伤模型的报道。在这里，我们从成人真皮成纤维细胞衍生的神经干细胞中生成了自组织的 3D 人类神经类器官。这些人类神经类器官中的径向胶质细胞表现出人类大脑皮层趋势的特征，包括内层（脑室区）和外层（早期和晚期皮质板区）。这些数据表明神经类器官反映了人类大脑皮层独特的径向组织，并允许研究神经元增殖和成熟。为了利用这个 3D 模型，我们对神经类器官进行了缺氧损伤。我们研究了缺氧损伤和复氧后的神经元损伤和再生。有趣的是，缺氧损伤后，再氧合恢复了神经元细胞增殖，但不恢复神经元成熟。这项研究表明，由神经干细胞产生的人类神经类器官为药物筛选平台的开发和神经退行性疾病（包括缺氧性脑损伤）的个性化建模提供了新的机会。我们研究了缺氧损伤和复氧后的神经元损伤和再生。有趣的是，缺氧损伤后，再氧合恢复了神经元细胞增殖，但不恢复神经元成熟。这项研究表明，由神经干细胞产生的人类神经类器官为药物筛选平台的开发和神经退行性疾病（包括缺氧性脑损伤）的个性化建模提供了新的机会。我们研究了缺氧损伤和复氧后的神经元损伤和再生。有趣的是，缺氧损伤后，再氧合恢复了神经元细胞增殖，但不恢复神经元成熟。这项研究表明，由神经干细胞产生的人类神经类器官为药物筛选平台的开发和神经退行性疾病（包括缺氧性脑损伤）的个性化建模提供了新的机会。