title: A Mechanistic Collective Cell Model for Epithelial Colony Growth and Contact Inhibition.
abstract: We present a mechanistic hybrid continuum-discrete model to simulate the dynamics of epithelial cell colonies. Collective cell dynamics are modeled using continuum equations that capture plastic, viscoelastic, and elastic deformations in the clusters while providing single-cell resolution. The continuum equations can be viewed as a coarse-grained version of previously developed discrete models that treat epithelial clusters as a two-dimensional network of vertices or stochastic interacting particles and follow the framework of dynamic density functional theory appropriately modified to account for cell size and shape variability. The discrete component of the model implements cell division and thus influences cell size and shape that couple to the continuum component. The model is validated against recent in vitro studies of epithelial cell colonies using Madin-Darby canine kidney cells. In good agreement with experiments, we find that mechanical interactions and constraints on the local expansion of cell size cause inhibition of cell motion and reductive cell division. This leads to successively smaller cells and a transition from exponential to quadratic growth of the colony that is associated with a constant-thickness rim of growing cells at the cluster edge, as well as the emergence of short-range ordering and solid-like behavior. A detailed analysis of the model reveals a scale invariance of the growth and provides insight into the generation of stresses and their influence on the dynamics of the colonies. Compared to previous models, our approach has several advantages: it is independent of dimension, it can be parameterized using classical elastic properties (Poisson's ratio and Young's modulus), and it can easily be extended to incorporate multiple cell types and general substrate geometries.
authors.affiliation: Department of Mathematics, Technische Universität Dresden, Dresden, Germany. Electronic address: sebastian.aland@tu-dresden.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Aland
authors.affiliation: Department of Mathematics, Technische Universität Dresden, Dresden, Germany; Center for Advancing Electronics Dresden (CfAED), Technische Universität Dresden, Dresden, Germany.
authors.forename: Haralambos
authors.initials: H
authors.lastname: Hatzikirou
authors.affiliation: Department of Mathematics and Center for Complex Biological Systems, University of California Irvine, Irvine, California. Electronic address: lowengrb@math.uci.edu.
authors.forename: John
authors.initials: J
authors.lastname: Lowengrub
authors.affiliation: Department of Mathematics, Technische Universität Dresden, Dresden, Germany; Center for Advancing Electronics Dresden (CfAED), Technische Universität Dresden, Dresden, Germany; Center for Systems Biology Dresden (CSBD), Dresden, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Voigt
mesh_terms: D000465:Algorithms; D000818:Animals; D001696:Biomechanical Phenomena; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D048429:Cell Size; D003198:Computer Simulation; D004285:Dogs; D004548:Elasticity; D004847:Epithelial Cells / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D008938:Mitosis / Q000502:physiology; D008954:Models, Biological