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-mediated 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.
Highlights
One of the most characteristic property of a eukaryotic cell is the utterly high level of organization of its internal transport processes, in particular the vesicle-mediated cell transport
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
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
Summary
One of the most characteristic property of a eukaryotic cell is the utterly high level of organization of its internal transport processes, in particular the vesicle-mediated cell transport. It is a biological process where, e.g., soluble proteins either enter the cell or get released into the extracellular matrix, known as endo- or exocytosis. In case of the endocytosis, the selected cargo together with some plasma membrane lipids and extracellular fluid become fully internalized into the cell forming a spherical vesicle. Recent advances in imaging techniques allowed to examine the individual dynamics of secretory vesicles in vitro in more detail [10,11,12,13]
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