title: A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration.
abstract: It is now evident that the cell nucleus undergoes dramatic shape changes during important cellular processes such as cell transmigration through extracellular matrix and endothelium. Recent experimental data suggest that during cell transmigration the deformability of the nucleus could be a limiting factor, and the morphological and structural alterations that the nucleus encounters can perturb genomic organization that in turn influences cellular behavior. Despite its importance, a biophysical model that connects the experimentally observed nuclear morphological changes to the underlying biophysical factors during transmigration through small constrictions is still lacking. Here, we developed a universal chemomechanical model that describes nuclear strains and shapes and predicts thresholds for the rupture of the nuclear envelope and for nuclear plastic deformation during transmigration through small constrictions. The model includes actin contraction and cytosolic back pressure that squeeze the nucleus through constrictions and overcome the mechanical resistance from deformation of the nucleus and the constrictions. The nucleus is treated as an elastic shell encompassing a poroelastic material representing the nuclear envelope and inner nucleoplasm, respectively. Tuning the chemomechanical parameters of different components such as cell contractility and nuclear and matrix stiffnesses, our model predicts the lower bounds of constriction size for successful transmigration. Furthermore, treating the chromatin as a plastic material, our model faithfully reproduced the experimentally observed irreversible nuclear deformations after transmigration in lamin-A/C-deficient cells, whereas the wild-type cells show much less plastic deformation. Along with making testable predictions, which are in accord with our experiments and existing literature, our work provides a realistic framework to assess the biophysical modulators of nuclear deformation during cell transmigration.
authors.affiliation: Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xuan
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Mechanical Engineering, University College London, London, United Kingdom.
authors.forename: Emad
authors.initials: E
authors.lastname: Moeendarbary
authors.affiliation: Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York.
authors.forename: Philipp
authors.initials: P
authors.lastname: Isermann
authors.affiliation: Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Davidson
authors.affiliation: Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Chen
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Anya K
authors.initials: AK
authors.lastname: Burkart
authors.affiliation: Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York; Nancy C. and Peter E. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
authors.affiliation: Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: vshenoy@seas.upenn.edu.
authors.forename: Vivek B
authors.initials: VB
authors.lastname: Shenoy
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry* / Q000502:physiology*; D053144:Cell Nucleus Shape / Q000502:physiology*; D003198:Computer Simulation; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004548:Elasticity; D042783:Endothelial Cells / Q000737:chemistry / Q000502:physiology; D056656:Lab-On-A-Chip Devices; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D010539:Permeability; D011312:Pressure; D013314:Stress, Mechanical; D013312:Stress, Physiological / Q000502:physiology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000199:Actins; D014867:Water