Reverse-engineering the mechanical organization and rheology of epithelial tissues

The epithelium is a cohesive two-dimensional layer of cells attached to a fluid-filled fibrous matrix, which lines most free surfaces and cavities of the body. It serves as a protective barrier with tunable permeability, which must retain integrity in a mechanically active environment. Paradoxically, it must also be malleable enough to self-heal and remodel into functional 3D structures such as villi in our guts or tubular networks. Intrigued by these conflicting material properties, the main idea of this proposal is to view epithelial monolayers as living engineering materials. Unlike lipid bilayers or hydrogels, widely used in biotechnology, cultured epithelia are only starting to be integrated in organ-on-chip microdevices. As for any complex inert material, this program requires a fundamental understanding of the structure-property relationships, interpreted here as how subcellular structures and their biological regulation produce net effective material behaviors. At short time-scales epithelia exhibit solid-like behavior while at longer times they flow as a consequence of the only qualitatively understood dynamics of the cell-cell junctional network. Towards understanding epithelial rheology, we will combine a broad range of theoretical, computational and experimental methods. With quantitative understanding of the material properties of these cell sheets, we may be able to manipulate and use them efficiently to adopt pre-designed geometries, to perform physiological functions (biosensing, selective compartmentalization, secretion) or to test drugs in vitro in organ-on-chip technologies. Thus, besides providing fundamental mechanobiological understanding, this project will provide a framework to manipulate epithelia in bioinspired technologies.

This proposal is directly relevant to the Challenge Health, demographic change and well-being of the Spanish Strategy of Science, Technology and Innovation. Indeed, epithelial mechanics are fundamental in developmental processes and in adult life in health and disease. Furthermore, cultured epithelial monolayers are emerging as a central element in organ-on-chip or tissue regeneration strategies. The present proposal also addresses the Challenges defined in the European and Spanish research strategies by developing Essential Enabling Technologies (Tecnología Facilitadora Esencial) in the fields of Advanced Materials and Biotechnology.