Date Published: April 9, 2019
Publisher: Public Library of Science
Author(s): Aapo Tervonen, Teemu O. Ihalainen, Soile Nymark, Jari Hyttinen, Michael Koval.
Tight junctions are dynamic structures that are crucial in establishing the diffusion and electrical barrier of epithelial monolayers. Dysfunctions in the tight junctions can impede this barrier function and lead to many pathological conditions. Unfortunately, detailed understanding of the non-specific permeation pathway through the tight junctions, the so-called leak pathway, is lacking. We created computational models of the leak pathway to describe the two main barrier measures, molecular permeability and transepithelial electric resistance while using common structural dynamics. Our results showed that the proposed alternatives for the leak pathway, the bicellular strand opening dynamics and the tricellular pores, contribute together with distinct degrees, depending on the epithelium. The models can also capture changes in the tight junction barrier caused by changes in tight junction protein composition. In addition, we observed that the molecular permeability was markedly more sensitive to changes in the tight junction structure and strand dynamics compared with transepithelial electric resistance. The results highlight that our model creates a good methodological framework to integrate knowledge on the tight junction structure as well as to provide insights and tools to advance tight junction research.
Epithelial cell monolayers cover body surfaces and line different organs. These tissues separate the underlying organs from their surroundings by creating tight barriers, and cell-cell junctions play a crucial role in this process. The most significant components for the barrier function are the tight junctions (TJs). These dynamic structures bring the membranes of adjacent cells into close contact, and thus seal the paracellular space between them. Due to their important role in the epithelial function, it is not surprising that there are several diseases, such as inflammatory bowel disease and celiac disease, which are linked to dysfunctions in TJ proteins or in the TJ complexes themselves [1, 2]. In these pathological conditions, the epithelium usually becomes leaky , and thus rendering it unfit for its task. In the present work, we investigate the dynamic properties of the epithelial barrier by developing a computational model of TJ structure.
Tight junctions (TJs) are an indispensable part of the epithelia that form the barriers between many of the body’s compartments, and yet not enough is known about their structure or structural dynamics. In this work, we have developed a computational model of the dynamic TJ structure to study the origin and the properties of the leak pathway—the nonspecific permeation pathway through the TJs. This was done by simulating the epithelial molecular permeability of a PEG oligomer and transepithelial electrical resistance (TER) with the same structural strand dynamics for different epithelial monolayers and scenarios. The model combines the current knowledge and theory of the dynamic TJ structure into a computational framework.