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

Park, Dong Shin, Kozaki, Tatsuya, Tiwari, Satish Kumar, Moreira, Marco, Khalilnezhad, Ahad, Torta, Federico, Olivié, Nicolas, Thiam, Chung Hwee, Liani, Oniko, Silvin, Aymeric, Phoo, Wint Wint, Gao, Liang, Triebl, Alexander, Tham, Wai Kin, Gonçalves, Leticia, Kong, Wan Ting, Raman, Sethi, Zhang, Xiao Meng, Dunsmore, Garett, Dutertre, Charles Antoine, Lee, Salanne, Ong, Jia Min, Balachander, Akhila, Khalilnezhad, Shabnam, Lum, Josephine, Duan, Kaibo, Lim, Ze Ming, Tan, Leonard, Low, Ivy, Utami, Kagistia Hana, Yeo, Xin Yi, Di Tommaso, Sylvaine, Dupuy, Jean-William, Varga, Balazs, Karadottir, Ragnhildur Thora, Madathummal, Mufeeda Changaramvally, Bonne, Isabelle, Malleret, Benoit, Binte, Zainab Yasin, Wei Da, Ngan, Tan, Yingrou, Wong, Wei Jie, Zhang, Jinqiu, Chen, Jinmiao, Sobota, Radoslaw M., Howland, Shanshan W., Ng, Lai Guan, Saltel, Frédéric, Castel, David, Grill, Jacques, Minard, Veronique, Albani, Salvatore, Chan, Jerry K. Y., Thion, Morgane Sonia, Jung, Sang Yong, Wenk, Markus R., Pouladi, Mahmoud A., Pasqualini, Claudia, Angeli, Veronique, Cexus, Olivier N. F., Ginhoux, Florent·2023·Nature
DOI 10.1038/s41586-023-06713-1
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Abstract

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain 1 . 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 2-6 . The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development 7-10 . However, current approaches do not incorporate microglia or address their role in organoid maturation 11-21 . Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac) 22 . In organoid cocultures, 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 NPCs in the organoids. We also detected PLIN2 + lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogen…

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  • HNOs that incorporate microglia promote maturation and provide unique advantages as in vitro neuroimmune models.

    “Despite the limitations of organoid-based models, HNOs that incorporate microglia promote maturation97 and provide unique advantages as in vitro neuroimmune models98–103, which are increasingly becoming utilized.”

    From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [97]

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Authors
Park, D. S., Kozaki, T., Tiwari, S. K., Moreira, M., Khalilnezhad, A., Torta, F., Olivié, N., Thiam, C. H., Liani, O., Silvin, A., Phoo, W. W., Gao, L., Triebl, A., Tham, W. K., Gonçalves, L., Kong, W. T., Raman, S., Zhang, X. M., Dunsmore, G., Dutertre, C. A., Lee, S., Ong, J. M., Balachander, A., Khalilnezhad, S., Lum, J., Duan, K., Lim, Z. M., Tan, L., Low, I., Utami, K. H., Yeo, X. Y., Di Tommaso, S., Dupuy, J.-W., Varga, B., Karadottir, R. T., Madathummal, M. C., Bonne, I., Malleret, B., Binte, Z. Y., Wei Da, N., Tan, Y., Wong, W. J., Zhang, J., Chen, J., Sobota, R. M., Howland, S. W., Ng, L. G., Saltel, F., Castel, D., Grill, J., Minard, V., Albani, S., Chan, J. K. Y., Thion, M. S., Jung, S. Y., Wenk, M. R., Pouladi, M. A., Pasqualini, C., Angeli, V., Cexus, O. N. F., & Ginhoux, F.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-11-01
Volume
623
Issue
7986
Pages
397-405
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/s41586-023-06713-1
Cited by
239
References
20
Language
en
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