Deterministic model of dermal wound invasion incorporating receptor-mediated signal transduction and spatial gradient sensing

Biophys J. 2006 Apr 1;90(7):2297-308. doi: 10.1529/biophysj.105.077610. Epub 2006 Jan 13.

Abstract

During dermal wound healing, platelet-derived growth factor (PDGF) serves as both a chemoattractant and mitogen for fibroblasts, potently stimulating their invasion of the fibrin clot over a period of several days. A mathematical model of this process is presented, which accurately accounts for the sensitivity of PDGF gradient sensing through PDGF receptor/phosphoinositide 3-kinase-mediated signal transduction. Analysis of the model suggests that PDGF receptor-mediated endocytosis and degradation of PDGF allows a constant PDGF concentration profile to be maintained at the leading front of the fibroblast density profile as it propagates, at a constant rate, into the clot. Thus, the constant PDGF gradient can span the optimal concentration range for asymmetric phosphoinositide 3-kinase signaling and fibroblast chemotaxis, with near-maximal invasion rates elicited over a relatively broad range of PDGF secretion rates. A somewhat surprising finding was that extremely sharp PDGF gradients do not necessarily stimulate faster progression through the clot, because maintaining such a gradient through PDGF consumption is a potentially rate-limiting process.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biophysics / methods*
  • Cell Membrane / metabolism
  • Cell Movement
  • Cell Physiological Phenomena
  • Cell Proliferation
  • Chemotaxis
  • Diffusion
  • Endocytosis
  • Fibroblasts / metabolism*
  • Kinetics
  • Mice
  • Models, Biological
  • Models, Statistical
  • Models, Theoretical
  • Phosphatidylinositol 3-Kinases / metabolism
  • Platelet-Derived Growth Factor / metabolism
  • Platelet-Derived Growth Factor / physiology*
  • Receptors, Platelet-Derived Growth Factor / metabolism*
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Signal Transduction
  • Wound Healing*

Substances

  • Platelet-Derived Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Receptors, Platelet-Derived Growth Factor