title: Hierarchy of cellular decisions in collective behavior: Implications for wound healing.
abstract: Collective processes such as wound re-epithelialization result from the integration of individual cellular decisions. To determine which individual cell behaviors represent the most promising targets to engineer re-epithelialization, we examined collective and individual responses of HaCaT keratinocytes seeded upon polyacrylamide gels of three stiffnesses (1, 30, and 100 kPa) and treated with a range of epidermal growth factor (EGF) doses. Wound closure was found to increase with substrate stiffness, but was responsive to EGF treatment only above a stiffness threshold. Individual cell behaviors were used to create a partial least squares regression model to predict the hierarchy of factors driving wound closure. Unexpectedly, cell area and persistence were found to have the strongest correlation to the observed differences in wound closure. Meanwhile, the model predicted a relatively weak correlation between wound closure with proliferation, and the unexpectedly minor input from proliferation was successfully tested with inhibition by aphidicolin. Combined, these results suggest that the poor clinical results for growth factor-based therapies for chronic wounds may result from a disconnect between the individual cellular behaviors targeted in these approaches and the resulting collective response. Additionally, the stiffness-dependency of EGF sensitivity suggests that therapies matched to microenvironmental characteristics will be more efficacious.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Dr, Madison, WI, 53706 United States of America.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Wickert
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Dr, Madison, WI, 53706 United States of America.
authors.forename: Shaun
authors.initials: S
authors.lastname: Pomerenke
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Dr, Madison, WI, 53706 United States of America.
authors.forename: Isaiah
authors.initials: I
authors.lastname: Mitchell
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Dr, Madison, WI, 53706 United States of America.
authors.forename: Kristyn S
authors.initials: KS
authors.lastname: Masters
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, 1550 Engineering Dr, Madison, WI, 53706 United States of America.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Kreeger
mesh_terms: D002449:Cell Aggregation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology*; D016018:Least-Squares Analysis; D008954:Models, Biological; D012044:Regression Analysis; D014945:Wound Healing / Q000187:drug effects
chemical_list: D004815:Epidermal Growth Factor
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