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.
Authors
- Hadis Shakeri
- Carleigh A. O’Brien (ORCID: https://orcid.org/0000-0003-4549-0640)
- Liam Barry-Carroll (ORCID: https://orcid.org/0000-0002-3683-538X)
- Ria Roelandt (ORCID: https://orcid.org/0000-0001-9936-7555)
- Gilles Faron (ORCID: https://orcid.org/0000-0003-2603-7488)
- Diego Gómez‐Nicola (ORCID: https://orcid.org/0000-0002-5316-2682)
- Sophia Leduc (ORCID: https://orcid.org/0000-0002-4931-1999)
- Kiavash Movahedi (ORCID: https://orcid.org/0000-0002-0826-4399)
- Fazeela Yaqoob (ORCID: https://orcid.org/0000-0002-9058-9810)
- Hannah Van Hove (ORCID: https://orcid.org/0000-0002-0412-6474)
- Jonathan Bastos (ORCID: https://orcid.org/0000-0003-4862-4835)
- Mónica Vara‐Pérez (ORCID: https://orcid.org/0000-0001-6196-4696)
- David Gate (ORCID: https://orcid.org/0000-0003-0481-9657)
- Maria Breugelmans (ORCID: https://orcid.org/0000-0002-9070-2713)
- Leen Ali (ORCID: https://orcid.org/0000-0002-6782-2338)
- Karen De Vlaminck (ORCID: https://orcid.org/0000-0002-5595-1482)
- Myrthe Mampay (ORCID: https://orcid.org/0000-0002-4966-2721)
- Sonia I Lombroso (ORCID: https://orcid.org/0000-0003-2348-0417)
- Daliya Kancheva (ORCID: https://orcid.org/0000-0001-6222-0461)
- F. Chris Bennett (ORCID: https://orcid.org/0000-0003-2570-0620)
- Isabelle Scheyltjens (ORCID: https://orcid.org/0000-0002-2260-2921)
- Lynn van Olst (ORCID: https://orcid.org/0000-0001-7569-0470)
- Laura Meysman
- Vladislav Vlasov
- Ayla Line Lievens
Institutions
- Northwestern University (US)
- Children's Hospital of Philadelphia (US)
- Vrije Universiteit Brussel (BE)
- Southampton General Hospital (GB)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- VIB-UGent Center for Plant Systems Biology (BE)
- Translational Therapeutics (United States) (US)
- Universitair Ziekenhuis Brussel (BE)
- NutriNeuro (FR)
- VIB-UGent Center for Inflammation Research (BE)
- Institut Polytechnique de Bordeaux (FR)
- University of Pennsylvania (US)
- Mathys (Netherlands) (NL)
Publication Details
- Journal
- Immunity
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.immuni.2025.04.006
- Citations
- 41
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 34.53
Funders
- Fonds Wetenschappelijk Onderzoek
- H2020 European Research Council