Microglia innately develop within cerebral organoids

TLDR

Cerebral organoids are 3D stem cell‑derived models used to study the human brain, yet they lack mesodermal‑derived microglia, limiting their relevance to neural development and disease. The study aims to develop and characterize a microglia‑containing cerebral organoid model to investigate interactions among microglia, macroglia, and neurons in human brain development and disease. Microglia spontaneously arise within cerebral organoids, displaying ramified morphology, transcriptomic and inflammatory responses that closely match adult human microglia, and actively phagocytosing synaptic material.

Abstract

Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.