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Spatiotemporal models and simulations reveal the physical mechanisms that migrating cells sense and self-adapt to heterogeneous extracellular microenvironments

Chen, Xindong 2020. Spatiotemporal models and simulations reveal the physical mechanisms that migrating cells sense and self-adapt to heterogeneous extracellular microenvironments. PhD Thesis, Cardiff University.
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Abstract

Cell migration plays essential roles in many normal physiological and pathological processes, such as embryonic morphogenesis, wound healing, tissue renewal, nervous system development, cancer metastasis and autoimmune disorders. Both single cell migration and collective cell migration are powered by the actin-based lamellipodia, filopodia or invadopodia protrusions at their leading edges to migrate through extremely heterogeneous extracellular microenvironments. Although extensive experimental studies about cell migration have been conducted, it is unknown of the intracellular physical mechanisms of how migrating cells sense and adapt to the highly varying extracellular mechanical microenvironments. To address this, we construct the predictive spatiotemporal model of the lamellipodial branched actin network through simulating its realistic selfassembling process by encompassing key proteins and their highly dynamic interactions. Then, using finite element simulations, we quantitatively demonstrate the mechanical roles of individual intracellular proteins in regulating the elastic properties of the self-assembling network during cell migration. More importantly, we reveal a resistance-adaptive intracellular physical mechanism of cell migration: the lamellipodial branched actin network can sense the variations of immediate extracellular resistance through the bending deformations of actin filaments, and then adapt to the resistance by self-regulating its elastic properties sensitively through Arp2/3 nucleating, remodelling with F-actin, filamin-A and α-actinin and altering the filament orientations. Such resistance-adaptive behaviours are versatile and essential in driving cells to over-come the highly varying extracellular confinements. Additionally, it is deciphered that the actin filament bending deformation and anisotropic Poisson’s ratio effect of the branched actin network and Arp2/3 branching preference jointly determine why lamellipodium grows into a sheet-like structure and protrudes against resistance persistently. Our predictions Abstract IV are confirmed by published pioneering experiments. The revealed mechanism also can be applied to endocytosis and intracellular pathogens motion. The propulsive force of cell migration is based on actin filament polymerization. We propose a theoretical ‘bending-straightening elastic ratchet’ (BSER) model, which is based on geometrical nonlinearity deformation of continuum solid mechanics. Then, we develop the self-assembling spatiotemporal mathematical model of the polymerizing lamellipodial branched actin filaments propelling the leading edge protrusion under heterogeneous extracellular microenvironment, and perform large-scale spatial and temporal simulations by applying the BSER theoretical model. Our simulation realistically encompasses the stochastic actin filament polymerization, Arp2/3 complex branching, capping proteins inhibiting actin polymerization, curved LE membrane, rupture of molecular linkers and varying extracellular mechanical microenvironment. Strikingly, our model for the first time systematically predicts all important leading-edge behaviours of a migrating cell. More importantly, we reveal two very fundamental biophysical mechanisms that migrating cells sense and adapt their protruding force to varying immediate extracellular physical constraints, and that how migrating cells navigate their migratory path to in highly heterogeneous and complex extracellular microenvironments. Additionally, our BSER theoretical model and the underlying physical mechanism revealed here are also applicable to the propulsion systems of endocytosis, intracellular pathogen transport and dendritic spine formation in cortical neurons, which are powered by polymerization of branched actin filaments as well. Filopodia and invadopodia protrusions are the other two types of cell migration behaviours at their leading edges. Through three-dimensional assembling model of filopodial/invadopodial F-actin bundles and finite element simulations, we quantitatively identify how the highly dynamic assembling and disassembling actin filaments and binding and unbinding of crosslinking proteins, i.e., α-actinin and fascin, regulate Young’s modulus and buckling behaviours of Abstract V filopodia/invadopodia, respectively and combinedly. In addition, thermal induced undulation of actin filaments has an important influence on the buckling behaviours of filopodia/invadopodia. Compared with sheet-like lamellipodia, the finger-like filopodia/invadopodia have a much larger stiffness to protrude in extracellular microenvironment. Thus, they can cooperate with lamellipodia to complementarily split a channel in extracellular microenvironment and drive cell migration through the channel.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Engineering
Uncontrolled Keywords: Cell migration; Branched actin network; Elastic properties; Arp2/3 complex; Extracellular microenvironment; Spatiotemporal model and simulation.
Date of First Compliant Deposit: 21 July 2020
Last Modified: 16 Mar 2021 02:24
URI: http://orca.cardiff.ac.uk/id/eprint/133634

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