The dynamic behaviors of collective cells play a significant role in many physiological and pathological processes,e.g.,embryonic development and cancer metastasis.In this talk,theoretical models,numerical simulations...The dynamic behaviors of collective cells play a significant role in many physiological and pathological processes,e.g.,embryonic development and cancer metastasis.In this talk,theoretical models,numerical simulations,and experimental measurements are combined to investigate the dynamics of collective cells[1-5].First,cell division is the most fundamental process in embryonic development,tissue morphogenesis,and tumor growth.Experiments have suggested that mitotic cell division is regulated by intercellular cues.However,it remains unclear how cell-cell junctions affect the spindle machinery that determines the dividing orientation of cells.We establish a dynamic cell division model to explore the coupling of mechanical and chemical mechanisms,including cortical cell polarity,microtubule kinetics,cellular stiffness,internal osmotic pressure,and cell-cell junctions[2].The model reveals that the distributed forces of astral microtubules play a key role in encoding the instructive cell-cell junctional cues to orient the division of a rounded mitotic cell.By comparing with relevant experimental observations,we show that the model can not only predict the spindle orientation and positioning,but also capture the physical mechanisms of cell rounding.This work sheds light on the biophysical linkage between the cell cortex and the mitotic spindle,and holds potential applications in regulating cell division and sculpting tissue morphology.Second,collective cell migration occurs in a diversity of physiological processes such as wound healing,cancer metastasis,and embryonic morphogenesis.In the collective context,cohesive cells may move as a translational solid,swirl as a fluid,or even rotate like a disk,with scales ranging from several to dozens of cells.An active vertex model is presented to explore the regulatory roles of social interactions of neighboring cells and environmental confinements in collective cell migration in a confluent monolayer[2,3].It is found that the competition between two kinds of intercellular social interactions-local alignment(LA)and contact inhibition of locomotion(CIL)——drives the cells to self-organize into various dynamic coherent structures with a spatial correlation scale.The interplay between this intrinsic length scale and the external confinement dictates the migration modes of collective cells confined in a finite space.We also show that the LA-CIL coordination can induce giant density fluctuations in a confluent cell monolayer without gaps,which triggers the spontaneous breaking of orientational symmetry and leads to phase separation.Third,migrating cells constantly experience geometrical confinements in vivo,as exemplified by cancer invasion and embryo development.We investigate how intrinsic cellular properties and extrinsic channel confinements regulate the two-dimensional migratory dynamics of collective cells dynamics.We find that besides external confinement,active cell motility and cell crowdedness also shape the migration modes of collective cells.Further,the effects of active cell motility,cell crowdedness,and confinement size on collective cell migration can be integrated into a unified dimensionless parameter,defined as the cellular motility number(CMN),which mirrors the competition between active motile force and passive elastic restoring force of cells.A low CMN favors laminar-like cell flows,while a high CMN destabilizes cell motions,resulting in a series of mode transitions from a laminar phase to an ordered vortex chain,and further to a mesoscale turbulent phase.These findings not only explain recent experiments but also predict dynamic behaviors of cell collectives,such as the existence of an ordered vortex chain mode and the mode selection under non-straight confinements,which are experimentally testable across different epithelial cell lines.Fourth,self-organization of cells ordinarily displays collective dynamics that are crucial in biological processes such as embryogenesis and tumor invasion.We combine experiments and theory to investigate the energy landscape of self-sustained mesoscale cell turbulence emerging in confluent two-dimensional(2D)cell monolayers.We find that the enstrophy ofcollective cell flows scales linearly with the kinetic energy as the monolayer matures,defining a characteristic length scale of vortices.The kinetic energies of cells over time collapse to a family of probability distributions,which deviate from the classic Boltzmann distribution.The energy spectra for large wavenumbers exhibit a power-decaying law,with a scaling exponent markedly different from that in the classic 2D Kolmogorov-Kraichnan turbulence.It is found that these energetic features are near-universal for all different types of cells and substrates experimentalized.Our findings provide physical insights into fundamental aspects of self-organization in biological tissues.Fifth,periodic oscillations of collective cells occur in the morphogenesis and organogenesis of various tissues and organs.An oscillating cytodynamic model is presented by integrating the chemomechanical interplay between the RhoA effector signaling pathway and cell deformation [4,5].We show that both an isolated cell and a cell aggregate can undergo spontaneous oscillations as a result of Hopf bifurcation,upon which the system evolves into a limit cycle of oscillations.The dynamic characteristics are tailored by the mechanical properties of cells(e.g.,elasticity,contractility,and intercellular tension)and the chemical reactions involved in the RhoA effector signaling pathway.External forces are found to modulate the oscillation intensity of collective cells in the monolayer and to polarize their oscillations along the direction of external tension.The proposed cytodynamic model can recapitulate the prominent features of cell oscillations observed in a variety of experiments,including both isolated cells(e.g.,spreading mouse embryonic fibroblasts,migrating amoeboid cells,and suspending 3T3fibroblasts)and multicellular systems(e.g.,Drosophila embryogenesis and oogenesis).展开更多
基金supported by National Natural Science Foundation of China ( 11620101001,11672161, 11672227,11432008)the Thousand Young Talents Program of China
文摘The dynamic behaviors of collective cells play a significant role in many physiological and pathological processes,e.g.,embryonic development and cancer metastasis.In this talk,theoretical models,numerical simulations,and experimental measurements are combined to investigate the dynamics of collective cells[1-5].First,cell division is the most fundamental process in embryonic development,tissue morphogenesis,and tumor growth.Experiments have suggested that mitotic cell division is regulated by intercellular cues.However,it remains unclear how cell-cell junctions affect the spindle machinery that determines the dividing orientation of cells.We establish a dynamic cell division model to explore the coupling of mechanical and chemical mechanisms,including cortical cell polarity,microtubule kinetics,cellular stiffness,internal osmotic pressure,and cell-cell junctions[2].The model reveals that the distributed forces of astral microtubules play a key role in encoding the instructive cell-cell junctional cues to orient the division of a rounded mitotic cell.By comparing with relevant experimental observations,we show that the model can not only predict the spindle orientation and positioning,but also capture the physical mechanisms of cell rounding.This work sheds light on the biophysical linkage between the cell cortex and the mitotic spindle,and holds potential applications in regulating cell division and sculpting tissue morphology.Second,collective cell migration occurs in a diversity of physiological processes such as wound healing,cancer metastasis,and embryonic morphogenesis.In the collective context,cohesive cells may move as a translational solid,swirl as a fluid,or even rotate like a disk,with scales ranging from several to dozens of cells.An active vertex model is presented to explore the regulatory roles of social interactions of neighboring cells and environmental confinements in collective cell migration in a confluent monolayer[2,3].It is found that the competition between two kinds of intercellular social interactions-local alignment(LA)and contact inhibition of locomotion(CIL)——drives the cells to self-organize into various dynamic coherent structures with a spatial correlation scale.The interplay between this intrinsic length scale and the external confinement dictates the migration modes of collective cells confined in a finite space.We also show that the LA-CIL coordination can induce giant density fluctuations in a confluent cell monolayer without gaps,which triggers the spontaneous breaking of orientational symmetry and leads to phase separation.Third,migrating cells constantly experience geometrical confinements in vivo,as exemplified by cancer invasion and embryo development.We investigate how intrinsic cellular properties and extrinsic channel confinements regulate the two-dimensional migratory dynamics of collective cells dynamics.We find that besides external confinement,active cell motility and cell crowdedness also shape the migration modes of collective cells.Further,the effects of active cell motility,cell crowdedness,and confinement size on collective cell migration can be integrated into a unified dimensionless parameter,defined as the cellular motility number(CMN),which mirrors the competition between active motile force and passive elastic restoring force of cells.A low CMN favors laminar-like cell flows,while a high CMN destabilizes cell motions,resulting in a series of mode transitions from a laminar phase to an ordered vortex chain,and further to a mesoscale turbulent phase.These findings not only explain recent experiments but also predict dynamic behaviors of cell collectives,such as the existence of an ordered vortex chain mode and the mode selection under non-straight confinements,which are experimentally testable across different epithelial cell lines.Fourth,self-organization of cells ordinarily displays collective dynamics that are crucial in biological processes such as embryogenesis and tumor invasion.We combine experiments and theory to investigate the energy landscape of self-sustained mesoscale cell turbulence emerging in confluent two-dimensional(2D)cell monolayers.We find that the enstrophy ofcollective cell flows scales linearly with the kinetic energy as the monolayer matures,defining a characteristic length scale of vortices.The kinetic energies of cells over time collapse to a family of probability distributions,which deviate from the classic Boltzmann distribution.The energy spectra for large wavenumbers exhibit a power-decaying law,with a scaling exponent markedly different from that in the classic 2D Kolmogorov-Kraichnan turbulence.It is found that these energetic features are near-universal for all different types of cells and substrates experimentalized.Our findings provide physical insights into fundamental aspects of self-organization in biological tissues.Fifth,periodic oscillations of collective cells occur in the morphogenesis and organogenesis of various tissues and organs.An oscillating cytodynamic model is presented by integrating the chemomechanical interplay between the RhoA effector signaling pathway and cell deformation [4,5].We show that both an isolated cell and a cell aggregate can undergo spontaneous oscillations as a result of Hopf bifurcation,upon which the system evolves into a limit cycle of oscillations.The dynamic characteristics are tailored by the mechanical properties of cells(e.g.,elasticity,contractility,and intercellular tension)and the chemical reactions involved in the RhoA effector signaling pathway.External forces are found to modulate the oscillation intensity of collective cells in the monolayer and to polarize their oscillations along the direction of external tension.The proposed cytodynamic model can recapitulate the prominent features of cell oscillations observed in a variety of experiments,including both isolated cells(e.g.,spreading mouse embryonic fibroblasts,migrating amoeboid cells,and suspending 3T3fibroblasts)and multicellular systems(e.g.,Drosophila embryogenesis and oogenesis).
