Computational modeling of extracellular mechanotransduction.
Mechanotransduction may occur through numerous mechanisms, including potentially through autocrine signaling in a dynamically changing extracellular space. We developed a computational model to analyze how alterations in the geometry of an epithelial lateral intercellular space (LIS) affect the concentrations of constitutively shed ligands inside and below the LIS. The model employs the finite element method to solve for the concentration of ligands based on the governing ligand diffusion-convection equations inside and outside of the LIS, and assumes idealized parallel plate geometry and an impermeable tight junction at the apical surface. Using the model, we examined the temporal relationship between geometric changes and ligand concentration, and the dependence of this relationship on system characteristics such as ligand diffusivity, shedding rate, and rate of deformation. Our results reveal how the kinetics of mechanical deformation can be translated into varying rates of ligand accumulation, a potentially important mechanism for cellular discrimination of varying rate-mechanical processes. Furthermore, our results demonstrate that rapid changes in LIS geometry can transiently increase ligand concentrations in underlying media or tissues, suggesting a mechanism for communication of mechanical state between epithelial and subepithelial cells. These results underscore both the plausibility and complexity of the proposed extracellular mechanotransduction mechanism.
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
Nikola
N
Kojić
Milos
M
Kojić
Daniel J
DJ
Tschumperlin
D000818:Animals; D019898:Autocrine Communication; D003198:Computer Simulation; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology; D005110:Extracellular Space / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D040542:Mechanotransduction, Cellular; D008954:Models, Biological; D016211:Transforming Growth Factor alpha / Q000378:metabolism
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor