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Breaking into the brain- basement membranes and the perivascular niche

Project description

An in vitro model of the perivascular niche

The microenvironment around blood capillaries is known as the perivascular niche and plays an important role in various conditions, including neuroinflammation. The scope of the B3M project funded by the European Research Council is to study the perivascular niche of cerebral vessels by recreating it in vitro. Using hydrogels with tunable properties as a scaffold and endothelial cells derived from induced pluripotent stem cells, researchers will recapitulate the architecture and function of the in vivo perivascular niche. The in vitro system will allow investigation of the cellular and molecular events that dictate leukocyte penetration of the perivascular niche leading to neuroinflammation.

Objective

In neuroinflammation leukocytes reside for several days in the perivascular niche of cerebral blood vessels - defined by the basal surface of the endothelium, the endothelial basement membrane (BM) and an outer parenchymal BM with associated astrocyte endfeet (Fig. 1) - a poorly studied site but of utmost fundamental and clinical relevance. This site is also emerging as harbouring genetically distinct resident cell populations, the function of which are unclear. BMs define the perivascular niche and the sealed nature of this compartment in an unknown manner. B3M will explore the perivascular niche of cerebral vessels. Using our new dextran-hydrogel with tuneable adhesive, stiffness and degradability properties and cerebral endothelial cells derived from induced pluripotent stem cells (iPSC) we will recreate the subendothelial site; we will sequentially increase its complexity to reflect the in vivo spatial arrangement of cells and BMs, within the most correctly mimicked environmental properties, in a system that permits perfusion with immune cells and live imaging. Parallel ex vivo and synthetic approaches will further break down the complexity of this site into discrete steps and using multiscale imaging of new split-cre transgenic mice we will track, target and profile perivascular cells lacking BM receptors. Studies to date on leukocyte entry into the brain focus on endothelial properties or immune cell behaviour with little consideration of the 3D relationship between cellular and BM barriers and their functional interdependence. My unique knowledge on extracellular matrix structure/function of cerebral vessels and leukocyte migration into the brain, allows me to identify key elements of the perivascular niche and how they can be mimicked in vitro and targeted in vivo. B3M’s cross-disciplinary approach will decipher cellular and molecular events occurring after leukocyte penetration of the endothelium in the perivascular niche, shedding light on a black box.

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2021-ADG

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Host institution

UNIVERSITAET MUENSTER
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 300 451,00
Address
SCHLOSSPLATZ 2
48149 Muenster
Germany

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Region
Nordrhein-Westfalen Münster Münster, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 2 300 451,00

Beneficiaries (1)

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