Proteomics

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Proteomic analysis of human brain organoids

ABSTRACT: Microglia are specialised brain-resident macrophages that arise from primitive macrophages colonising the embryonic brain. Microglia contribute to multiple aspects of brain development, but their precise roles in early human brain remain poorly understood due to limited access to relevant tissues. The generation of brain organoids from induced human pluripotent stem cells (iPSC) recapitulates some key features of human embryonic brain development, but current approaches do not incorporate microglia and thus are lacking. Here, we generated microglia-sufficient brain organoids by co-culturing brain organoids with primitive-like macrophages generated from the same human iPSC (iMac). In organoid co-cultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro), and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters which were taken up by NPC in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brain. Overall, our approach significantly advances current human brain organoid approaches by incorporating microglial cells, illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPC leading to improved neurogenesis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell

SUBMITTER: Dupuy Jean-William  

LAB HEAD: Florent Ginhoux

PROVIDER: PXD044406 | Pride | 2025-11-26

REPOSITORIES: Pride

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Publications

iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.

Park Dong Shin DS   Kozaki Tatsuya T   Tiwari Satish Kumar SK   Moreira Marco M   Khalilnezhad Ahad A   Torta Federico F   Olivié Nicolas N   Thiam Chung Hwee CH   Liani Oniko O   Silvin Aymeric A   Phoo Wint Wint WW   Gao Liang L   Triebl Alexander A   Tham Wai Kin WK   Gonçalves Leticia L   Kong Wan Ting WT   Raman Sethi S   Zhang Xiao Meng XM   Dunsmore Garett G   Dutertre Charles Antoine CA   Lee Salanne S   Ong Jia Min JM   Balachander Akhila A   Khalilnezhad Shabnam S   Lum Josephine J   Duan Kaibo K   Lim Ze Ming ZM   Tan Leonard L   Low Ivy I   Utami Kagistia Hana KH   Yeo Xin Yi XY   Di Tommaso Sylvaine S   Dupuy Jean-William JW   Varga Balazs B   Karadottir Ragnhildur Thora RT   Madathummal Mufeeda Changaramvally MC   Bonne Isabelle I   Malleret Benoit B   Binte Zainab Yasin ZY   Wei Da Ngan N   Tan Yingrou Y   Wong Wei Jie WJ   Zhang Jinqiu J   Chen Jinmiao J   Sobota Radoslaw M RM   Howland Shanshan W SW   Ng Lai Guan LG   Saltel Frédéric F   Castel David D   Grill Jacques J   Minard Veronique V   Albani Salvatore S   Chan Jerry K Y JKY   Thion Morgane Sonia MS   Jung Sang Yong SY   Wenk Markus R MR   Pouladi Mahmoud A MA   Pasqualini Claudia C   Angeli Veronique V   Cexus Olivier N F ONF   Ginhoux Florent F  

Nature 20231101 7986

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain<sup>1</sup>. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues<sup>2-6</sup>. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development<sup>7-10</sup>. However,  ...[more]

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