title: Leader cell positioning drives wound-directed collective migration in TGFβ-stimulated epithelial sheets.
abstract: During wound healing and cancer metastasis, cells are frequently observed to migrate in collective groups. This mode of migration relies on the cooperative guidance of leader and follower cells throughout the collective group. The upstream determinants and molecular mechanisms behind such cellular guidance remain poorly understood. We use live-cell imaging to track the behavior of epithelial sheets of keratinocytes in response to transforming growth factor β (TGFβ), which stimulates collective migration primarily through extracellular regulated kinase 1/2 (Erk1/2) activation. TGFβ-treated sheets display a spatial pattern of Erk1/2 activation in which the highest levels of Erk1/2 activity are concentrated toward the leading edge of a sheet. We show that Erk1/2 activity is modulated by cellular density and that this functional relationship drives the formation of patterns of Erk1/2 activity throughout sheets. In addition, we determine that a spatially constrained pattern of Erk1/2 activity results in collective migration that is primarily wound directed. Conversely, global elevation of Erk1/2 throughout sheets leads to stochastically directed collective migration throughout sheets. Our study highlights how the spatial patterning of leader cells (cells with elevated Erk1/2 activity) can influence the guidance of a collective group of cells during wound healing.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Chapnick
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309 xuedong.liu@colorado.edu.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Liu
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004847:Epithelial Cells; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D051899:Smad2 Protein / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D020825:T-Box Domain Proteins; C574705:TBR1 protein, human; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human