Role of fluid membranes in cell-glycocalyx interactions under flow


PhD / Long term visitor's project

Cell capture at the blood vessel wall is a critical physiological process: red blood cell adhesion should be avoided to prevent blood clots, and the adhesion of circulating immune and stem cells under flow is  precisely regulated for appropriate immune and inflammatory responses and tissue repair. The initial interaction is mediated by the endothelial glycocalyx, a soft coat on the vessel wall that is rich in the extracellular matrix polysaccharide hyaluronan (HA), and our team has recently shed light on the complex interplay between biochemical interactions and mechanical properties that defines cell adhesion  under flow. Using a molecularly defined in vitro system, we have shown that the softness of a model glycocalyx (a well-defined HA brush)  repels red blood cell mimetics, while cell mimetics bearing CD44 (a widespread receptor that can bind to HA) exhibit stabilized rolling and indent the HA coat.

 

Here, we aim to improve our understanding of the biochemical-mechanical interplay during cell capture at the glycocalyx by focussing on two yet uncharted aspects:

  • How does te mobility of  receptors in the fluid cell membrane affect cell attachment to soft surfaces under flow?
  • How does the endothelial glycocalyx regulate cell attachment to ligands that reside deep inside the glycocalyx, at the endothelial cell surface?

We will tackle these questions by 1) including fluid membranes allowing reorganization of the receptors on the cell mimetic surface; and 2) complexifying our glycocalyx model by addition  of surface adhesion molecules. Building on experimental protocols previously developed in our group, we will study circulating  cell/glycocalyx interactions under flow. We will extend our current ‘minimal’ theoretical model as required to reproduce the experimental data and to pinpoint the relevant physical parameters governing cell  capture at the glycocalyx. Finally, we will confirm the biological relevance of our findings by monitoring attachment on our biomimetic surfaces of cells expressing controlled levels of the appropriate receptors.

Most published works have largely ignored the influence of the endothelial glycocalyx on adhesion to surface receptors under flow, because controlling glycocalyx properties on cells in vivo and in vitro remains challenging. The proposed research overcomes this limitation and will permit to revisit our understanding of the first steps of cell adhesion in the context of blood circulation. In addition, it will provide important experimental data to explore soft matter concepts such as superselectivity, elastohydrodynamics and force/diffusion interplay, along with their modelling, and identify key physical mechanisms of ‘soft adhesion’ under flow.


CONTACTS

  • PI: Delphine Débarre
  • Co-PI: Ralf Richter (visitor)
  • PhD student:

PARTNERS

  • LIPhy
  • School of Biomedical Sciences and School of Physics and
    Astronomy (University of Leeds, UK)

 

FUNDING

  • Tec21
  • University of Leeds