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dc.contributor.advisorBrugge, Joan S.
dc.contributor.authorNg, Mei Rosa
dc.date.accessioned2013-03-05T16:54:39Z
dash.embargo.terms2014-10-05en_US
dc.date.issued2013-03-05
dc.date.submitted2012
dc.identifier.citationNg, Mei Rosa. 2012. Mechanical Regulation of Epithelial Cell Collective Migration. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:10578en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10364613
dc.description.abstractCell migration is a fundamental biological process involved in tissue development, wound repair, and diseases such as cancer metastasis. It is a biomechanical process involving the adhesion of a cell to a substratum, usually an elastic extracellular matrix, as well as the physical contraction of the cell driven by intracellular actomyosin network. In the migration of cells as a group, known as collective migration, the cells are also physically linked to one another through cell-cell adhesions. How mechanical interactions with cell substratum and with neighboring cells regulate movements during collective migration, nevertheless, is poorly understood. To address this question, the effects of substrate stiffness on sheet migration of MCF10A epithelial cells were systematically analyzed. Speed, persistence, directionality and coordination of individual cells within the migrating sheet were all found to increase with substrate stiffening. Substrate stiffening also enhanced the propagation of coordinated movement from the sheet edge into the monolayer, which correlated with an upregulation of myosin-II activity in sheet edge cells. This mechano-response was dependent on cadherin-mediated cell-cell adhesions, which are required for the transmission of directional cue. Importantly, myosin-II contractility modulated cadherin- dependent cell-cell coordination, suggesting that contractile forces at cadherin adhesions regulate collective migration. To measure forces transmitted through cell-cell adhesions, a quantitative approach was developed in which cell-cell forces were deduced from cell-substrate traction forces, based on force balance principles and simple cell mechanics modeling. This method enabled the analysis of cell-cell mechanical interactions in small cell clusters of complex topology. The dynamic fluctuations of cell-cell forces over time revealed that force transmission between non-adjacent cells is typically limited, but is enhanced when the cell across which forces are being transmitted has reduced myosin-IIA or talin-1. This suggests that cells in a group may differentially regulate their levels of myosin-II contractility and cell-matrix mechanotransduction to promote longer-range force transmission during collective migration. Together, the results in this dissertation led to a working model of collective cell migration as regulated by cell-matrix mechanical properties and cell-cell mechanical interactions. This model, as well as the quantitative techniques developed here, will drive future studies on the mechanisms underlying collective migration.en_US
dc.language.isoen_USen_US
dash.licenseMETA_ONLY
dc.subjectCellular biologyen_US
dc.subjectBiophysicsen_US
dc.subjectBiomechanicsen_US
dc.subjectcell-cell coordinationen_US
dc.subjectcell trackingen_US
dc.subjectepithelial sheeten_US
dc.subjectmechanotransductionen_US
dc.subjectstiffnessen_US
dc.subjecttraction forceen_US
dc.titleMechanical Regulation of Epithelial Cell Collective Migrationen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorNg, Mei Rosa
dash.embargo.until10000-01-01
thesis.degree.date2012en_US
thesis.degree.disciplineCell and Developmental Biologyen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberShah, Jageshen_US
dc.contributor.committeeMemberToker, Alexen_US
dc.contributor.committeeMemberLauffenburger, Douglasen_US
dash.contributor.affiliatedNg, Mei Rosa


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