Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

3D spheroids have emerged as powerful drug discovery tools given their high-throughput screening (HTS) compatibility. Here, we established a method for generating functional neural spheroids with differentiated human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes at cell type c...

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Bibliographic Details
Published in:bioRxiv 2022-05
Main Authors: Strong, Caroline, Kundu, Srikanya, Boutin, Molly, Yu-Chi, Chen, Wilson, Kelli, Lee, Emily M, Ferrer, Marc
Format: Article
Language:English
Subjects:
Alzheimer's disease
Astrocytes
Bioengineering
Brain
Calcium (intracellular)
Calcium signalling
Cell differentiation
Disease
Drug abuse
Drug addiction
Enkephalins
Genetic engineering
High-throughput screening
Mimicry
Movement disorders
Neurodegenerative diseases
Neurological diseases
Parkinson's disease
Pluripotency
Spheroids
Stem cells
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Summary:3D spheroids have emerged as powerful drug discovery tools given their high-throughput screening (HTS) compatibility. Here, we established a method for generating functional neural spheroids with 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 modelling, drug testing, and formation of assembloids to model neurocircuitry. We developed disease models for Alzheimer's and Parkinson's Disease through incorporating genetically engineered cells into spheroids, and Opioid Use Disorder by chronically treating spheroids with DAMGO. We reversed baseline functional deficits in each disease model with clinically approved treatments and showed that assembloid activity can be chemogenetically manipulated. Here, we lay the groundwork for brain region-specific spheroids as a robust functional assay platform for HTS studies. Competing Interest Statement The authors have declared no competing interest.
ISSN:2692-8205
DOI:10.1101/2022.05.04.490442