In this study, we investigated the role of microglia in early human brain development by creating brain organoids that included microglia-like cells. Microglia are brain-resident macrophages that play a crucial role in brain development, but their precise functions in humans remain unclear due to limited access to human brain tissue. We developed a method to generate microglia-sufficient brain organoids by coculturing them with primitive macrophages derived from human induced pluripotent stem cells. These macrophages differentiated into microglia-like cells (iMicro) that influenced neuronal progenitor cell (NPC) differentiation, reducing NPC proliferation and promoting axon formation. Mechanistically, iMicro contained lipid droplets (PLIN2+), which exported cholesterol and its esters, which were taken up by NPCs. We also observed similar lipid droplets in microglia in both mouse and human embryonic brains. Our approach significantly advances current human brain organoid models by incorporating microglial cells, revealing a lipid-mediated interaction between microglia and NPCs that promotes neurogenesis and offering new insights into brain development.
DOI: 10.1038/s41586-023-06713-1
