Deterministic model of dermal wound invasion incorporating receptor-mediated signal transduction and spatial gradient sensing.
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.
Haugh
Jason M
JM
Department of Chemical & Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, USA. jason_haugh@ncsu.edu
D000818:Animals; D001703:Biophysics / Q000379:methods*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002468:Cell Physiological Phenomena; D049109:Cell Proliferation; D002633:Chemotaxis; D004058:Diffusion; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D008962:Models, Theoretical; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014945:Wound Healing
D010982:Platelet-Derived Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor