Human iPSC-derived microglia-containing 3D brain region-specific neural spheroids for disease modeling and therapeutic development 2118
Year: 2025
Type: article
Abstract: Description Microglia are the primary resident immune cells of the brain. Despite accumulating evidence of the microglial involvement in neurological diseases such as Parkinson’s disease (PD), there remains a lack of physiologically relevant human neural models that recapitulate microglial contributions to physiological and pathological brain states to accelerate therapeutics discovery. To address this gap, we developed a protocol to make high throughput screening (HTS)-compatible 3D tri-culture neural spheroids via a scaffold-free aggregation of differentiated hiPSCs-derived neurons, astrocytes, and microglia. These neural spheroids mimic brain-region-specific cell-type composition and display distinct calcium oscillation that respond to compound treatment making them uniquely suitable as functional assays for drug screening. Here, we show that: (1) microglia in tri-culture spheroids exhibit a range of functional activities including phagocytosis, motility, inflammatory responses towards pathogen-associated molecules, and predictable pharmacological responses; (2) microglia incorporation alters spontaneous calcium oscillation in healthy spheroids, implicating microglia-neuron interactions; (3) healthy microglia exhibit neuroprotective functions by rescuing PD-associated functional deficit in neural spheroids. Together, we showcase a novel 3D functional tri-culture neural HTS platform for studying microglia in healthy and disease conditions which could facilitate therapeutic development. Funding Sources This research was supported in part by the Intramural/Extramural research program of the NCATS, NIH. Topic Categories Neuroimmunology (NEUR)
Source: The Journal of Immunology
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416446115
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