Towards a virtual cornea - an agent-based model to study interactions between the cells and layers of the cornea under homeostasis and following chemical exposure.

Corneal injuries following chemical exposure differ in severity and reversibility. Various in vivo, ex vivo, and in vitro experimental methods attempt to predict whether exposure will lead to severe (corrosive), moderate, mild, or no irritancy but differ in their ability to prognosticate human-relevant eye irritation outcome. A detailed computational model of corneal injury at the multi-cellular level (depicting individual cells and biochemical processes in detail) which could predict these adverse outcomes would enable limitless virtual experiments. To improve the spatial and dynamic understanding of corneal chemical hazard, we built a multicellular agent-based model in the CompuCell3D modeling environment that aims to recapitulate complex cell behaviors underlying homeostasis and wound healing of the stratified epithelial layer and the stroma. The model represents a two-dimensional sagittal section of the limbal area with stem and transit-amplifying cells and a stratified epithelium layer keeping the same structure seen in its biological archetype, with a bilayer of superficial cells, two to three layers of wing cells, a single layer of basal cells attached to the basement membrane, and immune cells, bounded by virtual spaces to represent the tear layer and Bowman's membrane. Beneath this epithelial membrane lies an area representing the stroma with keratinocyte cells. Homeostasis in the epithelial layer implements signal information (cytokines, growth factors) and other factors can be added to more completely simulate the emergent wound-healing behavior where tear composition changes after injury, having higher levels of EGF (proliferation and migration), TGF-α (mitogen), HGF (proliferation and migration, promotes wound healing), KGF (proliferation), and IGF (proliferation), in the regulation of composite cellular behavior and multicellular interactions on proliferation and cell migration to the wounded site. These changes in the microenvironment activate quiescent limbal stem cells to proliferate and differentiate into transient-amplifying cells, which also proliferate and consequently differentiate into the other cell types present in the stratified epithelium layer. This mechanism is enough to heal mild and moderate wounds that avoid damaging the basement membrane. In cases of severe injury, other systems, including vascular and myeloid, participate in the repair of the Bowman's membrane and the stroma. This prototype virtual corneal model aims to define a more mechanistic human-relevant classification scheme, predict the time of recovery from each of those injuries, and offer potential explanations for the corneal anomalies (erosions and corneal ulcers) after severe damage and simulated responses to bioactivity data from various in vitro models of corneal toxicity. This will help toxicologists better understand critical events in cornea-chemical exposures as well as predict human-relevant adverse outcomes. Disclaimer: this abstract does not necessarily reflect USEPA policy.
Additional authors: J. A. Glazier1; T. B. Knudsen2; and C. Mahony3 1Department of Intelligent Systems Engineering and Biocomplexity Institute, Indiana University, Bloomington, IN; 2Center for Computational Toxicology and Exposure, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC; and 3Procter & Gamble, Technical Centre, Reading, United Kingdom.

Towards a virtual cornea - an agent-based model to study interactions between the cells and layers of the cornea under homeostasis and following chemical exposure.

Thursday, July 20 at 6:00pm

Joel Vanin

"Towards a virtual cornea - an agent-based model to study interactions between the cells and layers of the cornea under homeostasis and following chemical exposure."

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