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Aapo Tervonen, Daniel García León, Niina Onnela, Soile Nymark, Jari Hyttinen; Dynamics of Epithelial Tight Junction as Molecular and Electric Barrier - A Computational Approach. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4242.
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© ARVO (1962-2015); The Authors (2016-present)
Epithelial tissues, such as retinal pigment epithelium, separate compartments from each other and regulate solute transfer between compartments. Tight junctions (TJs) between epithelial cells are the main structures forming the barrier, hindering molecular diffusion and ion movement, which are characterized by permeability and transepithelial electric resistance (TER). TJs consist of networking strands of transmembrane molecules that interact with the neighboring cells’ respective molecules, and they are a highly dynamic structure: the strands break and remodel constantly. This leads to two diffusion pathways: the size-dependent pathway through the small pores in the strands and size-independent pathway through the strands breaks. However, it is not well known how these dynamics govern the TJ permeability or TER. Thus, we construct a computational model, with the aim to describe how TJ remodeling affects epithelial permeability and electrical conductivity, based on TJ strand structure and dynamics.
The model is a finite element model based on the TJ strand structure and dynamics. Strand dynamics are modeled by a stochastic model with parameters describing physiological TJ properties, such as molecular stability, time scale of the dynamics, and the small pore structure in the strands. The simulations are conducted with the same geometries for 8 molecular sizes (150−500 Da) and for the TER. In the end, the results of the TJ-scale model will be implemented into an epithelial-scale model describing the molecular and electric hindrance.
Similarly to measured values, the modeling results show clear discrimination of the permeability based on the size of the diffusing molecule. Varying the values of parameters governing the break dynamics lead to changes in permeability in the size-independent pathway, whereas varying the parameters describing the pore pathway leads to changes only in the permeability of the small molecules.
With our computational model, we are able to gain new knowledge of the TJs, especially what structural and dynamical components affect the barrier properties. In the future, we hope to combine this model with intracellular regulatory model to connect the regulatory processes as well as disease scenarios with the TJ structure and dynamics.
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