Invited Talk

Mechanisms of cellular penetration of vascular basement membranes - how biophysics could help us better understand this process

Xueli Zhang, Huiyu Wang, Jian Song, Lydia Sorokin

University of Muenster, Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15 48149 Münster, Germany

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While considerable information is available on how leukocytes navigate through the loose interstitial matrix of the stroma of tissues, comparatively little is known about penetration of basement membranes (BMs), tight protein networks that separate tissue compartments and designed to limit the movement of both cells and soluble molecules. In vivo imaging in our laboratory has revealed that penetration of the endothelial BM represents the time limiting step in extravasation, taking up to 40 min compared to the 3-4 min required to penetrate the endothelial monolayer. We have shown that the laminins, integral BMs components, play a critical role in this step. Endothelial BMs of postcapillary venules show ubiquitous distribution of laminin 411 (composed of α4β1γ1 chains) and patchy distribution of laminin 511 (α5β1γ1). In vivo inflammatory models involving T lymphocytes and neutrophils, indicate that sites containing little or no laminin 511 are the preferred sites of leukocyte extravasation. In vitro studies have shown that laminin 511 is highly adhesive for both neutrophils and T cells and inhibits migration in particular of T cells. Laminin 511 is known to self assemble into a 2D network, while laminin 411 has compromised networking ability due to truncated C-terminal domains. Preliminary work from our lab suggests that such structural differences result in differences in BM flexibility. Ex vivo analyses of intact BMs isolated from laminin ï�¡4 knockout mice (Lama4-/-) and endothelial specific laminin ï�¡5 knockout mice (Tie2cre/Lama5-/-) show that the presence of laminin 511 decreases BM flexibility, raising the possibility that the laminins may also contribute to mechanical signals transduced to leukocytes during extravasation. We are currently addressing this possibility using in vitro microchannel experiments that aim at mimicking the physical constraints that leukocytes undergo during migration across BMs and permit distinction between molecular versus mechanical signals.