Breaking into the brain- basement membranes and the perivascular niche

Introduction

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). This is a poorly studied site but of utmost fundamental and clinical relevance.

Resident Cell Populations

This site is also emerging as harboring genetically distinct resident cell populations, the function of which is unclear. BMs define the perivascular niche and the sealed nature of this compartment in an unknown manner.

Project Overview

B3M will explore the perivascular niche of cerebral vessels. Using our new dextran-hydrogel with tunable adhesive, stiffness, and degradability properties, along with cerebral endothelial cells derived from induced pluripotent stem cells (iPSC), we will recreate the subendothelial site.

Increasing Complexity

We will sequentially increase its complexity to reflect the in vivo spatial arrangement of cells and BMs, within the most accurately mimicked environmental properties, in a system that permits perfusion with immune cells and live imaging.

Methodology

Parallel ex vivo and synthetic approaches will further break down the complexity of this site into discrete steps. Using multiscale imaging of new split-cre transgenic mice, we will track, target, and profile perivascular cells lacking BM receptors.

Current Research Gaps

Studies to date on leukocyte entry into the brain focus on endothelial properties or immune cell behavior, with little consideration of the 3D relationship between cellular and BM barriers and their functional interdependence.

Unique Expertise

My unique knowledge of 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.

Conclusion

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.