Specification of CNS macrophage subsets occurs postnatally in defined niches

Masuda, Takahiro; Amann, Lukas; Monaco, Gianni; Sankowski, Roman; Staszewski, Ori; Krueger, Martin; Gaudio, Francesca Del; He, Liqun; Paterson, Neil; Nent, Elisa; Fernández-Klett, Francisco; Yamasaki, Ayato; Frosch, Maximilian; Fliegauf, Maximilian; Bosch, Lance Fredrick Pahutan; Ulupinar, Hatice; Hagemeyer, Nora; Schreiner, Dietmar; Dorrier, Cayce; Tsuda, Makoto; Grothe, Claudia; Joutel, Anne; Daneman, Richard; Betsholtz, Christer; Lendahl, Urban; Knobeloch, Klaus–Peter; Lämmermann, Tim; Priller, Josef; Kierdorf, Katrin; Prinz, Marco

doi:10.1038/s41586-022-04596-2

Cited by 153 publications

(174 citation statements)

References 66 publications

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“…In our experiments, the origin(s) of ED1-positive cells were not assessed and may represent resident and/or recruited population(s). Accordingly, future work should investigate precise lineage(s) of phagocytes in EPS/PAS to elucidate the existence of any functional zonations 28 . Since this work examined afferent PVS in mice, perivenous spaces should be studied and comparative anatomy of PVS should be investigated in human brains that are comprised of larger vessels.…”

Section: Discussionmentioning

confidence: 99%

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease

et al. 2022

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Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. The degree of pial coverage correlates with macrophage density and phagocytosis of CSF tracer. In vivo imaging confirms transpial influx of CSF tracer, suggesting a role of pia in CSF filtration, but not flow restriction. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer’s disease. Moreover, pial thickness correlates with improved CSF flow and reduced β-amyloid deposits in PVS of old mice. We show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

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Section: Discussionmentioning

confidence: 99%

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease

et al. 2022

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“…To independently evaluate the possibility that microglia are derived not only from CD206 - yolk sac progenitors but also from CD206 + cells (Masuda et al ., 2022), and if so, to newly explore when such a macrophage-to-microglia seeding could occur during brain development, we performed comprehensive immunohistochemistry using frozen sections (∼20 μm thick), focusing on whether the intramural cells positive for CX3CR1 (a common marker for the macrophage and microglia lineages) were also positive for CD206 and/or the purinergic receptor P2RY12, a specific marker for microglia ( Fig. 1A, B ).…”

Section: Resultsmentioning

confidence: 99%

“…Despite this proximity of embryonic BAMs to embryonic brain parenchyma, a previous study by Utz et al reported that the fates of microglia and BAMs are differentially determined prior to their colonization into the brain, based on the fact that a progenitor subset for BAMs (positive for CD206) and another subset for microglia (negative for CD206) can be separately identified in the yolk sac (Utz et al, 2020). However, a new fate-mapping study by Masuda et al has shown that CD206 + cells still have a considerable degree of developmental potential to flexibly choose a differentiation step to microglia, suggesting that a part of the total microglial cell population in the brain parenchyma may be supplied via the CD206 + lineage cells during the period between E9.5 and postnatal day (P) 14 (Masuda et al, 2022). Similar competence for flexible differentiation in CD206 + lineage cells has previously been suggested in tissue-resident macrophages (Mass et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Border-associated macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia

Hattori

Kato

Murayama

et al. 2022

Preprint

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The relationships between microglia and macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated labeling, we found that a group of intraventricular macrophages belonging to border-associated macrophages (BAMs), which were abundantly observed along the inner surface of the mouse cerebral wall at embryonic day 12, frequently entered the brain wall. Immunohistochemistry of the tracked cells showed that postinfiltrative BAMs acquired microglial properties while losing a macrophage phenotype. We also found that the intraventricular BAMs were supplied transepithelially from the roof plate. Thus, this study demonstrates that the ″roof plate→ventricle→cerebral wall″ route is an essential path for microglial colonization into the embryonic mouse brain.

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“…Furthermore, modulation of Notch regulates the severity of graft-versus-host reactions [ 99 , 100 ]. Modulation of T-cell responses also extends to experimental models for asthma [ 101 , 102 ], and recently, a role for Notch3 in regulating perivascular macrophages has been revealed [ 103 ].…”

Section: The Role Of Notch Signaling In the Tumor Microenvironmentmentioning

confidence: 99%

Roles of Notch Signaling in the Tumor Microenvironment

D’Assoro

Leon‐Ferre

Braune

et al. 2022

IJMS

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The Notch signaling pathway is an architecturally simple signaling mechanism, well known for its role in cell fate regulation during organ development and in tissue homeostasis. In keeping with its importance for normal development, dysregulation of Notch signaling is increasingly associated with different types of tumors, and proteins in the Notch signaling pathway can act as oncogenes or tumor suppressors, depending on the cellular context and tumor type. In addition to a role as a driver of tumor initiation and progression in the tumor cells carrying oncogenic mutations, it is an emerging realization that Notch signaling also plays a role in non-mutated cells in the tumor microenvironment. In this review, we discuss how aberrant Notch signaling can affect three types of cells in the tumor stroma—cancer-associated fibroblasts, immune cells and vascular cells—and how this influences their interactions with the tumor cells. Insights into the roles of Notch in cells of the tumor environment and the impact on tumor-stroma interactions will lead to a deeper understanding of Notch signaling in cancer and inspire new strategies for Notch-based tumor therapy.

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Specification of CNS macrophage subsets occurs postnatally in defined niches

Cited by 153 publications

References 66 publications

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease

Border-associated macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia

Roles of Notch Signaling in the Tumor Microenvironment

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