title: Predictive Analysis of Mechanistic Triggers and Mitigation Strategies for Pathological Scarring in Skin Wounds.
abstract: Wound fibrosis (i.e., excessive scar formation) is a medical problem of increasing prevalence, with poorly understood mechanistic triggers and limited therapeutic options. In this study, we employed an integrated approach that combines computational predictions with new experimental studies in mice to identify plausible mechanistic triggers of pathological scarring in skin wounds. We developed a computational model that predicts the time courses for six essential cell types, 18 essential molecular mediators, and collagen, which are involved in inflammation and proliferation during wound healing. By performing global sensitivity analyses using thousands of model-simulated wound-healing scenarios, we identified five key processes (among the 90 modeled processes) whose dysregulation may lead to pathological scarring in wounds. By modulating a subset of these key processes, we simulated fibrosis in wounds. Moreover, among the 18 modeled molecular mediators, we identified TGF-β and the matrix metalloproteinases as therapeutic targets whose modulation may reduce fibrosis. The model predicted that simultaneous modulation of TGF-β and matrix metalloproteinases would be more effective in treating excessive scarring than modulation of either therapeutic target alone. Our model was validated with previously published and newly generated experimental data, and suggested new in vivo experiments.
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702; and.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Nagaraja
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois, Chicago, IL 60612.
authors.forename: Lin
authors.identifier: 0000-0001-8530-2363
authors.initials: L
authors.lastname: Chen
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois, Chicago, IL 60612.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois, Chicago, IL 60612.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois, Chicago, IL 60612.
authors.forename: David
authors.identifier: 0000-0002-7747-7216
authors.initials: D
authors.lastname: Fine
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois, Chicago, IL 60612.
authors.forename: Luisa A
authors.identifier: 0000-0002-4842-1547
authors.initials: LA
authors.lastname: DiPietro
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702; and jaques.reifman.civ@mail.mil.
authors.forename: Jaques
authors.initials: J
authors.lastname: Reifman
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702; and.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Mitrophanov
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000473:pathology*; D003198:Computer Simulation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D051379:Mice; D008810:Mice, Inbred C57BL