An integrated systems biology approach to understanding the rules of keratinocyte colony formation

Authored by Mike Holcombe, Tao Sun, Sheila MacNeil, Rod Smallwood, Simon Coakley, Phil McMinn

Date Published: 2007

DOI: 10.1098/rsif.2007.0227

Sponsors: United Kingdom Engineering and Physical Sciences Research Council (EPSRC)

Platforms: C

Model Documentation: Other Narrative Flow charts Pseudocode

Model Code URLs: http://www.flame.ac.uk/

Abstract

Closely coupled in vitro and in virtuo models have been used to explore the self-organization of normal human keratinocytes (NHK). Although it can be observed experimentally, we lack the tools to explore many biological rules that govern NHK self-organization. An agent-based computational model was developed, based on rules derived from literature, which predicts the dynamic multicellular morphogenesis of NHK and of a keratinocyte cell line (HaCat cells) under varying extracellular Ca++ concentrations. The model enables in virtuo exploration of the relative importance of biological rules and was used to test hypotheses in virtuo which were subsequently examined in vitro. Results indicated that cell-cell and cell-substrate adhesions were critically important to NHK self-organization. In contrast, cell cycle length and the number of divisions that transit-amplifying cells could undergo proved non-critical to the final organization. Two further hypotheses, to explain the growth behaviour of HaCat cells, were explored in virtuo an inability to differentiate and a differing sensitivity to extracellular calcium. In vitro experimentation provided some support for both hypotheses. For NHKs, the prediction was made that the position of stem cells would influence the pattern of cell migration post-wounding. This was then confirmed experimentally using a scratch wound model.

Tags

proliferation In-vitro Stem-cells Signal-transduction Extracellular-matrix Growth-factor Cell-cycle progression Human epidermal-keratinocytes Terminal differentiation Induced apoptosis