Advanced healthcare materialsDec 18, 2025

Immune Control of Lab-Grown Brain Region Models with Matching Microglia-Like Cells

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Differential responses to Alzheimer’s disease extracellular vesicles were observed in co-cultured organoids and microglia-like cells.

Microglia-like cells (MGCs) can be derived from human induced pluripotent stem cells (iPSCs) and integrated with forebrain cortical organoids.
The co-cultured organoids showed reduced pro-inflammatory gene expressions when stimulated by Alzheimer’s disease extracellular vesicles.
Treatment with extracellular vesicles from healthy MGCs or co-culture led to decreased expressions of IL-12β, iNOS, TREM2, and CASS4.
Gene regulation related to microglial activation and carbon metabolism was observed in the co-cultured organoids.
Proteomics and microRNA-sequencing of Alzheimer’s disease extracellular vesicles identified proteins and microRNAs involved in pathways such as mitophagy.

Simplified

Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment.

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Immune Control of Lab-Grown Brain Region Models with Matching Microglia-Like Cells

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