Skull bone marrow channels as immune gateways to the central nervous system

Mazzitelli, Jose A.; Pulous, Fadi E.; Smyth, Leon C. D.; Kaya, Zeynep; Rustenhoven, Justin; Moskowitz, Michael A.; Kipnis, Jonathan; Nahrendorf, Matthias

doi:10.1038/s41593-023-01487-1

Cited by 28 publications

(9 citation statements)

References 99 publications

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“…This pattern of origin and distribution of PCs closely coincides with TAMs from perivascular macrophages in the brain [51]. Since the cephalic bone marrow, which provides immunocompetent cells to cephalic organs, is derived from neural crest-derived skull bones [52], we can hypothesize that the first macrophages in the TME may be derived from skull bone marrow, entering the meninges and cerebrospinal fluid in the subarachnoid space and then penetrating into the brain parenchyma through Virchow-Robin spaces in contact with PCs. In this scenario, skull-derived macrophages may penetrate the initial tumor mass before blood-brain barrier (BBB) disruption and interact with PCs at the onset of GBM formation.…”

Section: Origin Of Cells In Glioma Tmesupporting

confidence: 54%

Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression

Martinez-Morga,

Garrigos,

Rodriguez-Montero

et al. 2024

IJMS

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Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes’ anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system.

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Section: Origin Of Cells In Glioma Tmesupporting

confidence: 54%

Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression

Martinez-Morga,

Garrigos,

Rodriguez-Montero

et al. 2024

IJMS

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“…In particular, the calvarial–meningeal path allows transfer to the dura of unique myeloid cells ( 48 ), and of immature B lymphocytes ( 49 ). In the temporal bone, we found that marrow clusters were connected to the dura through channels of similar diameter as calvarial marrow ( 2 ), whereas connections to the inner ear appeared to coast the perilymphatic compartment rather than opening into it. It is important to consider that several regions of the otic capsule bone are porous ( 50 ), and that bone channels around the inner ear have been seen to fill with markers upon fluid injection in the inner ear.…”

Section: Discussionmentioning

confidence: 93%

“…In the brain, calvarial bone marrow is connected to the dura and CSF spaces through bone microvascular channels ( 43 ) which allow passage of immune cells, pathogens, and CSF signals triggering bone marrow cell release ( 2 ), supporting a major role of local bone marrow in neuroimmune communication. In particular, the calvarial–meningeal path allows transfer to the dura of unique myeloid cells ( 48 ), and of immature B lymphocytes ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

“…The inner ear and brain display several similar immune problems and solutions (e.g., swelling-induced compression, unique antigens, nonreplaceable information-critical cells, vascular barriers, local fluid compartments). In brain immunology, cranial bone marrow has recently been acknowledged as a major player, given its connections to the dura through bone channels allowing bidirectional transfer of immune cells and molecules [reviewed in ( 2 )]. Temporal bone marrow is also known to play a major local immune role in the middle ear (where it produces immune cells related to otitis responses, which can therefore occur without appreciable systemic reactions) ( 3 ) and around the endolymphatic sac (where it changes morphologically ( 4 ) and functionally ( 5 ) in response to immune challenges to the ear).…”

Section: Introductionmentioning

confidence: 99%

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Temporal bone marrow of the rat and its connections to the inner ear

Perin,

Cossellu,

Vivado

et al. 2024

Front. Neurol.

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Calvarial bone marrow has been found to be central in the brain immune response, being connected to the dura through channels which allow leukocyte trafficking. Temporal bone marrow is thought to play important roles in relation to the inner ear, but is still largely uncharacterized, given this bone complex anatomy. We characterized the geometry and connectivity of rat temporal bone marrow using lightsheet imaging of cleared samples and microCT. Bone marrow was identified in cleared tissue by cellular content (and in particular by the presence of megakaryocytes); since air-filled cavities are absent in rodents, marrow clusters could be recognized in microCT scans by their geometry. In cleared petrosal bone, autofluorescence allowed delineation of the otic capsule layers. Within the endochondral layer, bone marrow was observed in association to the cochlear base and vestibule, and to the cochlear apex. Cochlear apex endochondral marrow (CAEM) was a separated cluster from the remaining endochondral marrow, which was therefore defined as “vestibular endochondral marrow” (VEM). A much larger marrow island (petrosal non-endochondral marrow, PNEM) extended outside the otic capsule surrounding semicircular canal arms. PNEM was mainly connected to the dura, through bone channels similar to those of calvarial bone, and only a few channels were directed toward the canal periosteum. On the contrary, endochondral bone marrow was well connected to the labyrinth through vascular loops (directed to the spiral ligament for CAEM and to the bony labyrinth periosteum for VEM), and to dural sinuses. In addition, CAEM was also connected to the tensor tympani fossa of the middle ear and VEM to the endolymphatic sac. Endochondral marrow was made up of small lobules connected to each other and to other structures by channels lined by elongated macrophages, whereas PNEM displayed larger lobules connected by channels with a sparse macrophage population. Our data suggest that the rat inner ear is surrounded by bone marrow at the junctions with middle ear and brain, most likely with “customs” role, restricting pathogen spread; a second marrow network with different structural features is found within the endochondral bone layer of the otic capsule and may play different functional roles.

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“…Given the growing understanding of the role of infiltrating peripheral immune cells in CNS pathology and homeostasis, and the proposed role of the ChP as the immune gateway to the CNS, this model will allow for direct testing of the proposed role of the ChP as a crucial regulator of immune function in the brain 71–74 . Our data demonstrate that we identified a powerful mouse genetic tool that will facilitate examining the role of CSF in aging, neurorepair, and brain-peripheral immune interactions in CNS diseases, such as TBI 56,60 , stroke 55 , neurodegenerative and demyelinating diseases 75 .…”

Section: Discussionmentioning

confidence: 99%

The choroid plexus maintains ventricle volume and adult subventricular zone neuroblast pool, which facilitates post-stroke neurogenesis

Taranov,

Bedolla,

Iwasawa

et al. 2024

Preprint

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The brain's neuroreparative capacity after injuries such as ischemic stroke is contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here we report a mouse genetic tool (the ROSA26iDTR mouse line) for non-invasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at one-month post-ablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the MCAo model of ischemic stroke, neuroblast migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important and novel role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke.

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Skull bone marrow channels as immune gateways to the central nervous system

Cited by 28 publications

References 99 publications

Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression

Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression

Temporal bone marrow of the rat and its connections to the inner ear

The choroid plexus maintains ventricle volume and adult subventricular zone neuroblast pool, which facilitates post-stroke neurogenesis

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