Manufacturing Uniform Cerebral Organoids for Neurological Disease Modeling and Drug Evaluation.

IF 8.1 Q1 ENGINEERING, BIOMEDICAL Biomaterials research Pub Date : 2024-11-06 eCollection Date: 2024-01-01 DOI:10.34133/bmr.0104
Hyowon Hong, Yesl Jun, Sae-Bom Yoon, Seoyoon Park, Jaemeun Lee, Jeong Woon Jang, Hye Jin Nam, Heeyeong Cho
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Abstract

Human cerebral organoids are promising tools for investigating brain development and the pathogenesis underlying neurological disorders. To use organoids for drug effectiveness and safety screening, the organoids dispensed into each well must be prepared under precisely the same conditions as the cells. Despite decades of extensive research on approaches to improve organoid generation, various challenges remain, such as low yields and heterogeneity in size and differentiation both within and between batches. Here, we newly established uniform cerebral organoids (UCOs) derived from induced pluripotent stem cells by optimizing organoid size and performing real-time monitoring of telencephalic differentiation marker expression. These organoids exhibited morphological uniformity and consistent expression of FOXG1 during telencephalic differentiation, with high productivity. Moreover, UCOs faithfully recapitulated early corticogenesis, concomitant with the establishment of neuroepithelial populations, cortical plate neurons, and glial cells. Furthermore, UCOs systematically developed neural networks and exhibited both excitatory and inhibitory electrophysiological signals when exposed to neurotransmission blockers. Neurodevelopmental disease models derived from UCOs manifested neurite outgrowth defects, which could be ameliorated with targeted drug treatment. We propose UCOs as an advanced platform with low organoid variations and high reproducibility for modeling both brain development and neurological diseases.

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为神经系统疾病建模和药物评估制造统一的脑有机体。
人脑器官组织是研究大脑发育和神经系统疾病发病机制的理想工具。要利用类器官进行药物有效性和安全性筛选,必须在与细胞完全相同的条件下制备分配到每个孔中的类器官。尽管数十年来对改进类器官生成的方法进行了广泛研究,但仍存在各种挑战,如产量低、批次内和批次间大小和分化不均等。在这里,我们通过优化类器官大小和实时监测端脑分化标记表达,新建立了由诱导多能干细胞衍生的均匀脑类器官(UCOs)。这些器官组织在端脑分化过程中表现出形态学上的一致性和FOXG1的一致表达,并具有很高的生产率。此外,UCOs忠实地再现了早期皮质的发生,同时建立了神经上皮细胞群、皮质板层神经元和神经胶质细胞。此外,UCOs 系统地发展了神经网络,并在暴露于神经传递阻断剂时表现出兴奋和抑制电生理信号。由 UCOs 衍生出的神经发育疾病模型表现出神经元突起生长缺陷,这些缺陷可以通过靶向药物治疗得到改善。我们建议将 UCOs 作为一种先进的平台,以其较低的类器官变异性和较高的可重复性为大脑发育和神经系统疾病建模。
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