Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1+ microglia
Immunity. 2025-04-01; :
DOI: 10.1016/j.immuni.2025.04.006
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1. Immunity. 2025 Apr 24:S1074-7613(25)00169-4. doi:
10.1016/j.immuni.2025.04.006. Online ahead of print.
Monocytes can efficiently replace all brain macrophages and fetal liver
monocytes can generate bona fide SALL1+ microglia.
Bastos J(1), O’Brien C(2), Vara-Pérez M(1), Mampay M(1), van Olst L(3),
Barry-Carroll L(4), Kancheva D(1), Leduc S(1), Lievens AL(1), Ali L(1), Vlasov
V(1), Meysman L(1), Shakeri H(1), Roelandt R(5), Van Hove H(1), De Vlaminck
K(1), Scheyltjens I(1), Yaqoob F(2), Lombroso SI(6), Breugelmans M(7), Faron
G(7), Gomez-Nicola D(8), Gate D(3), Bennett FC(9), Movahedi K(10).
Author information:
(1)Brain and Systems Immunology Laboratory, Brussels Center for Immunology,
Vrije Universiteit Brussel, Brussels, Belgium.
(2)Department of Psychiatry, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA.
(3)The Ken & Ruth Davee Department of Neurology, Northwestern University
Feinberg School of Medicine, Chicago, IL, USA.
(4)School of Biological Sciences, Southampton General Hospital, University of
Southampton, Southampton, UK; Nutrineuro, UMR 1286 INRAE, Bordeaux University,
Bordeaux INP, Bordeaux, France.
(5)VIB Single Cell Core, VIB, Ghent/Leuven, Belgium; Department of Biomedical
Molecular Biology, Ghent University, Ghent, Belgium.
(6)Department of Psychiatry, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and
Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
(7)Department of Obstetrics and Prenatal Medicine, UZ Brussel, VUB, Brussels,
Belgium.
(8)School of Biological Sciences, Southampton General Hospital, University of
Southampton, Southampton, UK.
(9)Department of Psychiatry, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA; Division of Neurology, Children’s Hospital
of Philadelphia, Philadelphia, PA, USA.
(10)Brain and Systems Immunology Laboratory, Brussels Center for Immunology,
Vrije Universiteit Brussel, Brussels, Belgium. Electronic address:
.
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.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2025.04.006
PMID: 40311613
Conflict of interest statement: Declaration of interests F.C.B. is a co-inventor
on a patent filed by The Board of Trustees of The Leland Stanford Junior
University (application 16/566,675) related to methods of microglia replacement.
F.C.B. holds shares in NovoGlia Inc. D.G. has been a consultant/adviser relating
to Alzheimer’s therapies for Merck and Novo Nordisk.