Microglia innately develop within cerebral organoids

Paul R. Ormel; Renata Vieira de Sá; Emma J. van Bodegraven; Henk Karst; Oliver Harschnitz; Marjolein A. M. Sneeboer; Lill Eva Johansen; Roland E. van Dijk; Nicky Scheefhals; Amber Berdenis van Berlekom; Eduardo Ribes Martínez; Sandra Kling; Harold D. MacGillavry; Leonard H. van den Berg; René S. Kahn; Elly M. Hol; Lot D. de Witte; R. Jeroen Pasterkamp

doi:10.1038/s41467-018-06684-2

Microglia innately develop within cerebral organoids

Paul R. Ormel, Renata Vieira de Sá, Emma J. van Bodegraven, Henk Karst, Oliver Harschnitz, Marjolein A. M. Sneeboer, Lill Eva Johansen, Roland E. van Dijk, Nicky Scheefhals, Amber Berdenis van Berlekom, Eduardo Ribes Martínez, Sandra Kling, Harold D. MacGillavry, Leonard H. van den Berg, René S. Kahn, Elly M. Hol, Lot D. de Witte, R. Jeroen Pasterkamp

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	4167
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06684-2
Publication status	Published - 1 Dec 2018
Externally published	Yes

Funding

We are grateful to the Netherlands Brain Bank (http://www.brainbank.nl) who provided us with the post mortem human brain tissue. We thank the MIND facility at the UMC Utrecht for their help. We are thankful to M.H.M. de Goeij for setting up the phagocytosis assay and Dr. R. F. Hevner (University of Washington, Seattle, WA) for providing us with the TBR1 antibody. Furthermore, we want to thank Vanessa Marques Donega for providing us with adult MG for an experiment and Yujie He for helping with ELISA assays. Lastly, we are grateful for the advice on bioinformatics from Mark K. Bakker and Onur Basak. This project was financially supported by: The Netherlands Organization for Scientific Research (NWO-VICI; to E.M.H. and R.J.P.), Parkinson fund #937409 and ZonMW memorabel #733050107 (to E.M.H.); Utrecht University Strategic Theme Dynamics of Youth, Stichting ALS Nederland; Prinses Beatrix Spierfonds (to R.J.P); L.D. W: Narsad Young investigator grant.

Funders	Funder number
NWO-VICI	937409
Netherlands Organization for Scientific Research
ZonMw	733050107
Universiteit Utrecht
Prinses Beatrix Spierfonds

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Ormel, P. R., Vieira de Sá, R., van Bodegraven, E. J., Karst, H., Harschnitz, O., Sneeboer, M. A. M., Johansen, L. E., van Dijk, R. E., Scheefhals, N., Berdenis van Berlekom, A., Ribes Martínez, E., Kling, S., MacGillavry, H. D., van den Berg, L. H., Kahn, R. S., Hol, E. M., de Witte, L. D., & Pasterkamp, R. J. (2018). Microglia innately develop within cerebral organoids. Nature Communications, 9(1), Article 4167. https://doi.org/10.1038/s41467-018-06684-2

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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.",

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Ormel, PR, Vieira de Sá, R, van Bodegraven, EJ, Karst, H, Harschnitz, O, Sneeboer, MAM, Johansen, LE, van Dijk, RE, Scheefhals, N, Berdenis van Berlekom, A, Ribes Martínez, E, Kling, S, MacGillavry, HD, van den Berg, LH, Kahn, RS, Hol, EM, de Witte, LD & Pasterkamp, RJ 2018, 'Microglia innately develop within cerebral organoids', Nature Communications, vol. 9, no. 1, 4167. https://doi.org/10.1038/s41467-018-06684-2

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AU - Harschnitz, Oliver

AU - Sneeboer, Marjolein A. M.

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AU - van Dijk, Roland E.

AU - Scheefhals, Nicky

AU - Berdenis van Berlekom, Amber

AU - Ribes Martínez, Eduardo

AU - Kling, Sandra

AU - MacGillavry, Harold D.

AU - van den Berg, Leonard H.

AU - Kahn, René S.

AU - Hol, Elly M.

AU - de Witte, Lot D.

AU - Pasterkamp, R. Jeroen

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Microglia innately develop within cerebral organoids

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