Numerical analysis of the impact of cytoskeletal actin filament density alterations onto the diffusive vesicle-mediated cell transport

Abstract

The interior of a eukaryotic cell is a highly complex composite material which consists of water, structural scaffoldings, organelles, and various biomolecular solutes. All these components serve as obstacles that impede the motion of vesicles. Hence, it is hypothesized that any alteration of the cytoskeletal network may directly impact or even disrupt the vesicle transport. A disruption of the vesicle-mediate cell transport is thought to contribute to several severe diseases and disorders, such as diabetes, Parkinson’s and Alzheimer’s disease, emphasizing the clinical relevance. To address the outlined objective, a multiscale finite element model of the diffusive vesicle transport is proposed on the basis of the concept of homogenization, owed to the complexity of the cytoskeletal network. In order to study the microscopic effects of specific nanoscopic actin filament network alterations onto the vesicle transport, a parametrized three-dimensional geometrical model of the actin filament network was generated on the basis of experimentally observed filament densities and network geometries in an adenocarcinomic human alveolar basal epithelial cell. Numerical analyzes of the obtained effective diffusion properties within two-dimensional sampling domains of the whole cell model revealed that the computed homogenized diffusion coefficients can be predicted statistically accurate by a simple two-parameter power law as soon as the inaccessible area fraction, due to the obstacle geometries and the finite size of the vesicles, is known. This relationship, in turn, leads to a massive reduction in computation time and allows to study the impact of a variety of different cytoskeletal alterations onto the vesicle transport. Hence, the numerical simulations predicted a 35% increase in transport time due to a uniformly distributed four-fold increase of the total filament amount. On the other hand, a hypothetically reduced expression of filament cross-linking proteins led to sparser filament networks and, thus, a speed up of the vesicle transport. Many vital processes in our eukaryotic cells and organs require an astonishingly precise routing of intermediate products to various intra- and extracellular destinations using vesicles as transporters. This can be illustrated by numerous examples, such as the production and destruction of proteins, the export of neurotransmitters or insulin to the extracellular domain, etc. However, the inside of a cell is tightly packed with numerous structural scaffoldings (filaments), which serve as obstacles and impede the vesicle motion. It is thought that any disturbances of the vesicle-mediated cell transport contribute to numerous degenerative diseases and disorders, which highlights the clinical relevance for investigating this intracellular transport mechanism by developing computational models and performing experimental studies. In this study, we numerically quantified how different specific alterations of the filament density inside a human lung cell—due to changed mechanical loadings or genetic disorders of proteins being responsible for filament branching—affect the diffusion of vesicles inside the intracellular fluid. Therefore, based on the concept of homogenization, a computationally efficient numerical method was developed and utilized to simulate the diffusion of vesicles inside the whole cell, considering the detailed structural information of the filament network.