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Human iPSC‐Derived Microglia Integrate Into Cerebral Organoids and Assume an In Vivo‐Like Phenotype

Emile Wogram,Felix Sümpelmann,Andrew Khalil,Anthony Flamier,Dongdong Fu,George W Bell,Rudolf Jaenisch

Published 2025 in European Journal of Neuroscience

ABSTRACT

Microglia, the brain‐resident macrophages, are critically involved in numerous physiological and pathological brain processes, including neoplasms, epilepsy, and neurodegeneration. However, investigating microglial function is notoriously difficult because they are extremely sensitive to changes in their environment and drastically alter their transcriptional state and morphology once they are isolated from the brain and cultured in vitro. In vivo experiments in mice are likewise limited because of vast differences between mouse and human microglia, particularly regarding the expression of disease‐associated genes. To overcome this issue, we developed a highly controlled in vitro cerebral organoid platform where human microglia adopt an in vivo‐like phenotype. This approach allows long‐term studies and high‐throughput analysis of in vivo‐like human microglia suitable for disease modeling and drug testing.

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