Microglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics

Dudiki, Tejasvi; Meller, Julia; Mahajan, Gautam; Liu, Huan; Zhevlakova, Irina; Stefl, Samantha; Witherow, Conner; Podrez, Eugene A.; Kothapalli, Chandrasekhar R.; Byzova, Tatiana V.

doi:10.1038/s41467-020-14787-y

Cited by 68 publications

(63 citation statements)

References 65 publications

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“…For example, in the embryonic brain, microglia are often localized to vascular junction points and depletion of all microglia is associated with a decrease in vascular complexity (Fantin et al 2010). Similar findings have been identified in the developing retina (Rymo et al 2011;Checchin et al 2006;Dudiki et al 2020). Our data demonstrating that microglia are localized to the vasculature prior to the arrival of the astrocyte endfeet could place microglia in a position to regulate fine-scale remodeling of the vasculature throughout the brain and/or help to maintain the BBB prior to astrocyte endfoot arrival.…”

Section: Possible Functions For Juxtavascular Microglia In the Healthsupporting

confidence: 56%

“…Studies in rodents and humans have shown that microglia associate with the vasculature in the developing CNS and live imaging in postnatal brain slices following traumatic injury or in embryonic mouse brain slices has suggested that microglia can migrate along the vasculature (Monier et al 2007;Fantin et al 2010;Smolders et al 2017;Grossmann et al 2002;Checchin et al 2006). Microglia have also been suggested to regulate vascular growth and complexity in the developing hindbrain and retina (Fantin et al 2010;Rymo et al 2011;Checchin et al 2006;Yoshiaki Kubota et al 2009;Dudiki et al 2020). Together, these studies provide evidence that there is microglia-vascular crosstalk, which requires further investigation in development, adulthood, and disease.…”

Section: Introductionmentioning

confidence: 87%

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A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

et al. 2020

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Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, 2 constantly extending and retracting their processes as they contact and functionally regulate 3 neurons and other glial cells. There is far less known about microglia-vascular interactions, 4 particularly under healthy steady-state conditions. Here, we use the male and female mouse 5 cerebral cortex to show that a higher percentage of microglia associate with the vasculature 6 during the first week of postnatal development compared to older ages and the timing of these 7 associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental 8 microglia-vascular associations were detected in the prenatal human brain. Using live imaging 9 in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature.

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Section: Possible Functions For Juxtavascular Microglia In the Healthsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 87%

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

et al. 2020

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“…CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint (which this version posted May 25, 2020. ; https://doi.org/10.1101/2020.05.25.110908 doi: bioRxiv preprint vascular growth and complexity in the developing hindbrain and retina (Fantin et al 2010;Rymo et al 2011;Checchin et al 2006;Yoshiaki Kubota et al 2009;Dudiki et al 2020). Together, these studies provide evidence that there is microglia-vascular crosstalk, which requires further investigation in development, adulthood, and disease.…”

Section: Introductionmentioning

confidence: 88%

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature

Mondo

Becker

Kautzman

et al. 2020

Preprint

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Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared to older ages and the timing of these associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the prenatal human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature.SIGNIFICANCE STATEMENTWe report the first extensive analysis of juxtavascular microglia in the healthy, developing and adult brain. Live imaging revealed that juxtavascular microglia within the cortex are highly motile and migrate along vessels as they are colonizing cortical regions. Using confocal, expansion, super-resolution, and electron microscopy, we determined that microglia associate with the vasculature at all ages in areas lacking full coverage astrocyte endfoot coverage and motility of juxtavascular microglia ceases as astrocyte endfeet more fully ensheath the vasculature. Our data lay the fundamental groundwork to investigate microglia-astrocyte crosstalk and juxtavascular microglial function in the healthy and diseased brain. They further provide a potential vascular-dependent mechanism by which microglia colonize the brain to later regulate neural circuit development.

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“…It has been shown that microglial depletion results in a sparser vascular network [ 26 , 27 ]. Duduki et al found that the lack of intracellular adapter Kindlin3, which within the CNS is exclusively expressed by microglia, leads to increased microglial contractility, dysregulation of the ERK pathway, overexpression of transforming growth factor-beta 1 (TGFβ1), and malformed vasculature within the retina [ 28 ]. This phenomenon could be remedied by either microglial depletion or by microglia-specific knockout of TGFβ1 in mouse models.…”

Section: Vasculogenesis and Angiogenesis As Viewed By Microgliamentioning

confidence: 99%

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

Florian

Şuşman

2021

IJMS

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Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.

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Microglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics

Cited by 68 publications

References 65 publications

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

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