Actin Turnover Required for Adhesion-Independent Bleb Migration

Abstract

Cell migration is critical for many vital processes, such as wound healing, as well as harmful processes, such as cancer metastasis. Experiments have highlighted the diversity in migration strategies employed by cells in physiologically relevant environments. In 3D fibrous matrices and confinement between two surfaces, some cells migrate using round membrane protrusions, called blebs. In bleb-based migration, the role of substrate adhesion is thought to be minimal, and it remains unclear if a cell can migrate without any adhesion complexes. We present a 2D computational fluid-structure model of a cell using cycles of bleb expansion and retraction in a channel with several geometries. The cell model consists of a plasma membrane, an underlying actin cortex, and viscous cytoplasm. Cellular structures are immersed in viscous fluid which permeates them, and the fluid equations are solved using the method of regularized Stokeslets. Simulations show that the cell cannot effectively migrate when the actin cortex is modeled as a purely elastic material. We find that cells do migrate in rigid channels if actin turnover is included with a viscoelastic description for the cortex. Our study highlights the non-trivial relationship between cell rheology and its external environment during migration with cytoplasmic streaming.

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds

“…The theoretical study of bleb nucleation (55)(56)(57)(58)(59)(60)(61) and bleb growth (53,(62)(63)(64) has been studied using coarse-grained mechanistic models. A few amoeboid/bleb-based motility biophysical models have also been recently developed, where the intracellular and extracellular spaces were assumed to behave as viscous fluids (47,48,(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75). Most of these models assume that plasma membrane and cortex are a single composite material.…”

“…However, the model by Lim et al (66) does not satisfy conservation of momentum, since it does not account for the forces exerted by the cortex on the cytoplasm as it moves through the crowded intracellular medium. Likewise, the model of Copos and Strychalski (67) introduces a cortical viscoelastic force that depends on a reference cortical configuration, as well as a steric interaction force with the walls; and the inclusion of these two forces does not guarantee that the total force exerted by the cell on the medium vanishes, potentially violating conservation of linear momentum as well. To address this gap, in the present study, we first develop a biophysical mechanistic model of bleb-based cell swimming in a viscoelastic medium to assess whether bleb-producing cells such as T cells can mechanically swim in the absence of adhesions, identify the key cellular components that regulate the motile capabilities of swimming cells, and quantify the theoretical maximum speed that a cell can achieve using this migration mechanism.…”

“…Bleb nucleation [57][58][59][60][61][62] and bleb growth 55,[63][64][65] have been studied theoretically using coarsegrained mechanistic models. In addition, a handful of amoeboid/bleb-based motility biophysical models have also been recently developed, where the intracellular and extracellular spaces were assumed to behave as viscous fluids 49,50,[66][67][68][69][70][71][72][73][74][75][76][77][78] . Most of these cell migration models assume that plasma membrane and cortex are a single composite material.…”

“…Most of these cell migration models assume that plasma membrane and cortex are a single composite material. Two of these studies, however account for the mechanical interactions between the intracellular viscous fluid, the actin cortex and the cell membrane 66,67 . However, the model by Lim et al 66 does not satisfy conservation of momentum, since it does not account for the forces exerted by the cortex on the cytoplasm as it moves through the crowded intracellular medium.…”

“…However, the model by Lim et al 66 does not satisfy conservation of momentum, since it does not account for the forces exerted by the cortex on the cytoplasm as it moves through the crowded intracellular medium. Likewise, the model of Copos and Strychalski 67 introduces a cortical viscoelastic force that depends on a reference cortical configuration, as well as a steric interaction force with the walls. Although the enforced no-penetration fluid flow condition at the boundaries ensures conservation of linear momentum in the fluid, the inclusion of these two forces does not guarantee that the total force exerted by the cell on the medium vanishes.…”