Computational Modeling of Epithelial Barrier Properties and Biomechanics

Epithelial tissues consist of tightly connected cells that line all our organs and form barriers between the inside and outside of the body. Many of the epithelial functions are dependent on the junctions between the cells: e.g., the tight junctions that form the primary barrier and the adherens junctions that transmit forces between the cells. Due to their role as barriers, epithelia are subjected to many harmful stimuli and are thus prone to many diseases. These diseases usually lead to the failure of the barrier as well as changes in epithelial tissue biomechanics. Therefore, to better understand epithelial homeostasis and disease processes, more knowledge is required on the structure and regulation of the barrier and the factors affecting the transmission of forces between the cells.

The typical measurements of epithelial barrier reflect the epithelium-wide properties and thus lack the resolution to address the barrier at the cellular or subcellular level. More advanced methods have been developed, but they also have challenges mainly due to the small size scale of the barrier-forming structures. Likewise, while many methods exist to study epithelial biomechanics, they can only provide a partial view of the whole system by themselves. The field of computational modeling can provide tools to guide and support these experimental methods. While there are only a few detailed models of the epithelial barriers, there is an abundance of models describing the mechanics of these tissues. However, these models usually lack the description of the mechanical microenvironment of the cells.

This thesis aims to improve our understanding of the biophysical aspects of epithelial physiology by using computational modeling to develop tools to study the barrier-forming components in epithelial tissue barriers, the structural dynamics of the barrier-forming tight junctions, the measurement sensitivity of the transepithelial electrical measurements, and the effect of microenvironment stiffness on the force transmission between epithelial cells.

The thesis work resulted in three models and one study conducted using a finite element method software. The models use a variety of different modeling methods. The model describing the components of a tissue barrier, more specifically the blood-retinal barrier in the eye, was a steady-state model based on the serial and parallel connection between the barrier components. Stochastic multicompartmental and resistor network models were used to describe the structural dynamics of the tight junctions. The model of the transepithelial electrical measurements was built and solved using the finite element method. Finally, a cell-based model was developed to study epithelial biomechanics.

The epithelial tissue barrier model indicated that the paracellular pathway between the epithelial cells, specifically the tight junctions, formed the governing permeation route for diffusion through the whole tissue. The results from the more detailed tight junction model suggested that the so-called leak pathway utilized by larger molecules would be formed by both the large pores in the tricellular junctions and the step-by-step diffusion through the structural dynamics of the bicellular strand network. Furthermore, we found that the dynamic strand network described in this model affected the measured molecular permeability and transepithelial resistance values differently, enabling separate regulation of these two properties. The finite element model of the electrode placement showed that the electrode positioning and measurement frequency heavily affected the measured area of the epithelium, but not the obtained values themselves. The final model on the epithelial mechanics indicated that the propagation of forces between cells is highly dependent on the substrate stiffness and that cells in confluent epithelium can transmit information on the microenvironment stiffness and its heterogeneities depending on their ability to resist deformations.

The models developed in this thesis help to guide the experimental work by creating platforms to produce testable hypotheses, optimize measurements, and analyze and quantify experimental results. Together with experimental work, computational models of epithelia provide a more complete view of the properties and relationship of the epithelial barrier and biomechanics to help us understand these essential tissues in health and in disease.