Maternal tamoxifen treatment expands the macrophage population of early mouse embryos

Rojo, Rocío; Ka, Sauter; Lefèvre, Lucas; Hume, David; Pridans, Clare

doi:10.1101/296749

Cited by 6 publications

(4 citation statements)

References 41 publications

(49 reference statements)

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“…These models rely on tamoxifen administration thus, it could be possible that BM-derived myeloid cell engraftment in the CNS results from an experimental or technical caveat related to toxin administration rather than the presence of an empty microglial niche. In line with this, a recent study has reported that tamoxifen expands macrophage populations and should be reconsidered as a neutral agonist in myeloid cell lineage studies 75 . Recent scrutiny has also been placed on the use of CSF1Ri, implicating long-term changes in bone-marrow derived macrophages 45 .…”

Section: Discussionmentioning

confidence: 78%

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Hohsfield¹,

Najafi²,

Ghorbanian³

et al. 2021

Preprint

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Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using sustained colony-stimulating factor 1 receptor inhibition, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from an important neurogenic niche, the subventricular zone, and associated white matter areas. These cells exhibit tremendous chemotaxis potential, migrating radially and tangentially in a dynamic wave and filling the brain in a distinct pattern, to fully replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit distinct phenotypic and functional profiles to endogenous microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into myeloid cell dynamics in an empty microglial niche without contributions from bone marrow-derived cells.

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Section: Discussionmentioning

confidence: 78%

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Hohsfield¹,

Najafi²,

Ghorbanian³

et al. 2021

Preprint

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“…The use of lineage tracing from BM-expressed drivers involves the use of tamoxifen, which has recently been identified as a neutral agonist in macrophage lineage tracing studies. A recent study has shown that tamoxifen treatment of pregnant mice induces a significant expansion of the embryonic macrophage population (Rojo et al, 2018).…”

mentioning

confidence: 99%

MAC2 is a long‐lasting marker of peripheral cell infiltrates into the mouse CNS after bone marrow transplantation and coronavirus infection

Hohsfield

Tsourmas

Ghorbanian

et al. 2022

Glia

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Microglia are the primary resident myeloid cells of the brain responsible for maintaining homeostasis and protecting the central nervous system (CNS) from damage and infection. Monocytes and monocyte-derived macrophages arising from the periphery have also been implicated in CNS pathologies, however, distinguishing between different myeloid cell populations in the CNS has been difficult. Here, we set out to develop a reliable histological marker that can assess distinct myeloid cell heterogeneity and functional contributions, particularly in the context of disease and/or neuroinflammation. scRNAseq from brains of mice infected with the neurotropic JHM strain of the mouse hepatitis virus (JHMV), a mouse coronavirus, revealed that Lgals3 is highly upregulated in monocyte and macrophage populations, but not in microglia. Subsequent immunostaining for galectin-3 (encoded by Lgals3), also referred to as MAC2, highlighted the high expression levels of MAC2 protein in infiltrating myeloid cells in JHMV-infected and bone marrow (BM) chimeric mice, in stark contrast to microglia, which expressed little to no staining in these models. Expression of MAC2 was found even 6-10 months following BM-derived cell infiltration into the CNS. We also demonstrate that MAC2 is not a specific label for plaqueassociated microglia in the 5xFAD mouse model, but only appears in a distinct subset of these cells in the presence of JHMV infection or during aging. Our data suggest that MAC2 can serve as a reliable and long-lasting histological marker for monocyte/ macrophages in the brain, identifying an accessible approach to distinguishing resident microglia from infiltrating cells in the CNS under certain conditions.

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“…myeloid cell lineage studies 80 . Recent scrutiny has also been placed on the use of CSF1Ri, implicating long-term changes in bone-marrow derived macrophages 55 .…”

mentioning

confidence: 99%

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Hohsfield

Najafi

Ghorbanian³

et al. 2021

eLife

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Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangentially in a dynamic wave filling the brain in a distinct pattern, to replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit similar phenotypic and transcriptional profiles to white matter-associated microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into repopulating microglia function and dynamics in the mouse brain.

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Maternal tamoxifen treatment expands the macrophage population of early mouse embryos

Cited by 6 publications

References 41 publications

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

MAC2 is a long‐lasting marker of peripheral cell infiltrates into the mouse CNS after bone marrow transplantation and coronavirus infection

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

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