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Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1 + microglia

Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1 + microglia
Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1 + microglia
Microglia and border-associated macrophages (BAMs) are critical for brain health, and their dysfunction is associated to disease. Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably to their embryonic counterparts and showed similar longevity. However, monocytes were unable to replicate the distinct identity of embryonically derived BAMs and microglia. Using xenotransplantation, we found that human monocytes exhibited similar behavior, enabling identification of putative Mo-Microglia in Alzheimer’s disease individuals. In mice and humans, monocyte ontogeny shaped their identity as brain macrophages. Importantly, mouse fetal liver monocytes exhibited a distinct epigenetic landscape and could develop a bona fide microglial identity. Our results illuminate brain macrophage development and highlight monocytes as an abundant progenitor source for brain macrophage replacement therapies.
border-associated macrophage, brain immunology, hematopoietic stem cell transplantation, microglia, microglia replacement, monocyte, neurodegeneration, ontogeny
1097-4180
1269-1288.e12
Bastos, Jonathan
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O’Brien, Carleigh
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Vara-Pérez, Mónica
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Mampay, Myrthe
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van Olst, Lynn
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Barry-Carroll, Liam Anthony
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Kancheva, Daliya
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Leduc, Sophia
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Lievens, Ayla Line
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Ali, Leen
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Vlasov, Vladislav
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Meysman, Laura
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Shakeri, Hadis
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Roelandt, Ria
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Van Hove, Hannah
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De Vlaminck, Karen
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Scheyltjens, Isabelle
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Yaqoob, Fazeela
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Lombroso, Sonia
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Breugelmans, Maria
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Faron, Gilles
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Gomez-Nicola, Diego
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Gate, David
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Bennett, F. Chris
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Movahedi, Kiavash
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Bastos, Jonathan
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O’Brien, Carleigh
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Vara-Pérez, Mónica
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Mampay, Myrthe
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van Olst, Lynn
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Barry-Carroll, Liam Anthony
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Kancheva, Daliya
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Leduc, Sophia
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Lievens, Ayla Line
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Ali, Leen
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Vlasov, Vladislav
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Meysman, Laura
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Shakeri, Hadis
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Roelandt, Ria
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Van Hove, Hannah
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De Vlaminck, Karen
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Scheyltjens, Isabelle
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Yaqoob, Fazeela
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Lombroso, Sonia
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Breugelmans, Maria
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Faron, Gilles
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Gomez-Nicola, Diego
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Gate, David
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Bennett, F. Chris
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Movahedi, Kiavash
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Bastos, Jonathan, O’Brien, Carleigh, Vara-Pérez, Mónica, Mampay, Myrthe, van Olst, Lynn, Barry-Carroll, Liam Anthony, Kancheva, Daliya, Leduc, Sophia, Lievens, Ayla Line, Ali, Leen, Vlasov, Vladislav, Meysman, Laura, Shakeri, Hadis, Roelandt, Ria, Van Hove, Hannah, De Vlaminck, Karen, Scheyltjens, Isabelle, Yaqoob, Fazeela, Lombroso, Sonia, Breugelmans, Maria, Faron, Gilles, Gomez-Nicola, Diego, Gate, David, Bennett, F. Chris and Movahedi, Kiavash (2025) Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1 + microglia. Immunity, 58 (5), 1269-1288.e12. (doi:10.1016/j.immuni.2025.04.006).

Record type: Article

Abstract

Microglia and border-associated macrophages (BAMs) are critical for brain health, and their dysfunction is associated to disease. Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably to their embryonic counterparts and showed similar longevity. However, monocytes were unable to replicate the distinct identity of embryonically derived BAMs and microglia. Using xenotransplantation, we found that human monocytes exhibited similar behavior, enabling identification of putative Mo-Microglia in Alzheimer’s disease individuals. In mice and humans, monocyte ontogeny shaped their identity as brain macrophages. Importantly, mouse fetal liver monocytes exhibited a distinct epigenetic landscape and could develop a bona fide microglial identity. Our results illuminate brain macrophage development and highlight monocytes as an abundant progenitor source for brain macrophage replacement therapies.

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Accepted/In Press date: 7 April 2025
e-pub ahead of print date: 30 April 2025
Published date: 13 May 2025
Keywords: border-associated macrophage, brain immunology, hematopoietic stem cell transplantation, microglia, microglia replacement, monocyte, neurodegeneration, ontogeny

Identifiers

Local EPrints ID: 500549
URI: http://eprints.soton.ac.uk/id/eprint/500549
DOI: doi:10.1016/j.immuni.2025.04.006
ISSN: 1097-4180
PURE UUID: d03d7e20-cb03-4c70-9533-a1830b4edeac
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

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Date deposited: 06 May 2025 16:34
Last modified: 03 Sep 2025 01:44

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Contributors

Author: Jonathan Bastos
Author: Carleigh O’Brien
Author: Mónica Vara-Pérez
Author: Myrthe Mampay
Author: Lynn van Olst
Author: Liam Anthony Barry-Carroll
Author: Daliya Kancheva
Author: Sophia Leduc
Author: Ayla Line Lievens
Author: Leen Ali
Author: Vladislav Vlasov
Author: Laura Meysman
Author: Hadis Shakeri
Author: Ria Roelandt
Author: Hannah Van Hove
Author: Karen De Vlaminck
Author: Isabelle Scheyltjens
Author: Fazeela Yaqoob
Author: Sonia Lombroso
Author: Maria Breugelmans
Author: Gilles Faron
Author: Diego Gomez-Nicola ORCID iD
Author: David Gate
Author: F. Chris Bennett
Author: Kiavash Movahedi

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