Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
Advanced Imaging and Microscopy Resource, National Institutes of Health, Bethesda, MD, 20892, USA.
Commun Biol. 2023 Nov 28;6(1):1211. doi: 10.1038/s42003-023-05582-8.
3D spheroids have emerged as powerful drug discovery tools given their high-throughput screening (HTS) compatibility. Here, we describe a method for generating functional neural spheroids by cell-aggregation of differentiated human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes at cell type compositions mimicking specific regions of the human brain. Recordings of intracellular calcium oscillations were used as functional assays, and the utility of this spheroids system was shown through disease modeling, drug testing, and formation of assembloids to model neurocircuitry. As a proof of concept, we generated spheroids incorporating neurons with Alzheimer's disease-associated alleles, as well as opioid use disorder modeling spheroids induced by chronic treatment of a mu-opioid receptor agonist. We reversed baseline functional deficits in each pilot disease model with clinically approved treatments and showed that assembloid activity can be chemogenetically manipulated. Here, we lay the groundwork for brain region-specific neural spheroids as a robust functional assay platform for HTS studies.
3D 球体已成为强大的药物发现工具，因为它们具有高通量筛选（HTS）的兼容性。在这里，我们描述了一种通过分化的人诱导多能干细胞（hiPSC）衍生神经元和星形胶质细胞的细胞聚集来生成功能性神经球体的方法，其细胞类型组成模拟人脑的特定区域。细胞内钙振荡的记录被用作功能测定，并且通过疾病建模、药物测试和组装体的形成来模拟神经回路，证明了该球体系统的实用性。作为概念验证，我们生成了包含具有阿尔茨海默病相关等位基因的神经元的球体，以及通过慢性治疗μ-阿片受体激动剂诱导的阿片类药物使用障碍建模球体。我们用临床批准的治疗方法逆转了每个试点疾病模型的基线功能缺陷，并表明可以对组装体的活性进行化学遗传操作。在这里，我们为脑区特异性神经球体奠定了基础，作为 HTS 研究的强大功能测定平台。
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