A proliferation control network model: the simulation of two-dimensional epithelial homeostasis

Area of Science:

• Computational biology
• Cell biology
• Tissue engineering

Background:

• Regulation of normal stratified epithelia homeostasis in vivo is not fully understood.
• In vitro studies have advanced understanding of cell proliferation and differentiation controls.
• Computer simulations offer a powerful approach to investigate complex cell proliferation networks.

Purpose of the Study:

• To investigate the regulation of stratified epithelia homeostasis in vivo using computer simulations.
• To model intracellular and extracellular controls of cell proliferation.
• To explore the influence of the microenvironment on cell proliferation and keratinocyte differentiation.

Main Methods:

• Developed a combined model of cell proliferation and spatial cell representation in 2D using Voronoi graphs.
• Incorporated intracellular controls (cyclins, Cyclin Dependent Kinases - CDKs, Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth/differentiation factors, integrins).
• Simulated tissue architecture, extracellular signals, and cell motility dynamically over time.

Main Results:

• Demonstrated the influence of the microenvironment on cell proliferation in basal epithelial layers.
• Illustrated the role of differential adherence in keratinocyte differentiation and upward migration.
• Highlighted the significant role of CDK inhibitors, particularly p27, in the Rb-dependent control of the G1 to S phase cell cycle transition.

Conclusions:

• Computer simulations provide valuable insights into in vivo epithelial homeostasis.
• The microenvironment and cell-cell interactions critically influence epithelial cell behavior.
• CDK inhibitors play a key role in regulating cell cycle progression within stratified epithelia.