Mechanobiology of the basement membrane

Abstract

The microenvironment (ME) of epithelial cells lies at the heart of the function and architecture of most organs. Epithelial cells define the function of the organ. The stroma ensures that the highly specialized MEs within an organ are correctly assembled. A key organising element of the ME is the rather stiff basement membrane (BM), which is the structural part that passively, through its mechanical rigidity and actively through signalling via its components separates the luminal epithelia from the stromal fibroblasts, creating and maintaining tissue polarity to ensure proper function of the organ. The primary goal of this work is to find universal features of the BM and epithelial cells across organs and to understand how the cells mechanobiology is influenced by the BM. The cells mechanobiology is defined by the interaction of the cells integrins with the BMs proteins, notably laminin, perlecan and collagen IV. Disturbing either of the interaction partners quickly leads to distinct new mechanobiological phenotypes of the epithelial cells, without the need for genetic modifications. Further, I will show that changes to the BM by cancer cells are a key step in forming invasive carcinomas which goes together with recent research that shows that the mechanics of epithelial cells and extra-cellular matrix (ECM) are fundamentally altered. In the case of BMs and the extracellular matrix in general, the mechanical properties are governed by the type of fibres and the state of cross-linking. The only tool available for characterizing this physical properties of cells and ECM components under physiological conditions is the atomic force microscope. It gives insight about stiffness and E-modulus on a sub-micrometer scale and is very sensitive to changes in the low Pascal-range. The combination with confocal light microscopy allows one to correlate changes in ridigity to cytoskeletion localisation, to understand what part of the cytoskeleton defines the mechanics and how this is changed by disturbing cell-BM interactions.