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Anisotropic environmental signals or polarized membrane ion/solute carriers can generate spatially varying intracellular gradients, leading to polarized cell dynamics. For example, the directional migration of neutrophils, galvanotaxis of glioblastoma, and water flux in kidney cells all result from the polarized distribution of membrane ion carriers and other intracellular components. The underlying physical mechanisms behind how polarized ion carriers interact with environmental signals are not well studied. Here, we use a physiology-relevant, physics-based mathematical model to reveal how ion carriers generate intracellular ion and voltage gradients. The model can discern the contribution of individual ion carriers to the intracellular pH gradient, electric potential, and water flux. We discover that an extracellular pH gradient leads to an intracellular pH gradient via chloride-bicarbonate exchangers, whereas an extracellular electric field leads to an intracellular electric potential gradient via passive potassium channels. In addition, mechanical-biochemical coupling can modulate actin distribution and flow, creating a biphasic dependence of cell speed on water flux. Moreover, we find that F-actin interaction with NHE alone can generate cell movement, even when other ion carriers are not polarized. Taken together, the model highlights the importance of cell ion dynamics in modulating cell migration and cytoskeletal dynamics.

Published by the American Physical Society2024 

Mammalian cell migration in open spaces requires F-actin polymerization and myosin contraction. While many studies have focused on myosin’s coupling to focal adhesion and stress fibers, the indirect effect of myosin contraction on cell migration through actin depolymerization is not well studied. In this work, we quantified how cell velocity and effective power output are influenced by the rate of actin depolymerization, which is affected by myosin contraction. In addition, we derived scaling laws to provide physical insights into cell migration. Model analysis shows that the cell migration velocity displays a biphasic dependence on the rate of actin depolymerization and myosin contraction. Our model further predicts that the effective cell energy output depends not only on the cell velocity but also on myosin contractility. The work has implications on in vivo processes such as immune response and cancer metastasis, where cells overcome barriers imposed by the physical environment. 

We have developed much understanding of actin-driven cell migration and the forces that propel cell motility. However, fewer studies focused on estimating the effective forces generated by migrating cells. Since cells in vivo are exposed to complex physical environments with various barriers, understanding the forces generated by cells will provide insights into how cells manage to navigate challenging environments. In this work, we use theoretical models to discuss actin-driven and water-driven cell migration and the effect of cell shapes on force generation. The results show that the effective force generated by actin-driven cell migration is proportional to the rate of actin polymerization and the strength of focal adhesion; the energy source comes from the actin polymerization against the actin network pressure. The effective force generated by water-driven cell migration is proportional to the rate of active solute flux and the coefficient of external hydraulic resistance; the energy sources come from active solute pumping against the solute concentration gradient. The model further predicts that the actin network distribution is mechanosensitive and the presence of globular actin helps to establish a biphasic cell velocity in the strength of focal adhesion. The cell velocity and effective force generation also depend on the cell shape through the intracellular actin flow field. 

Abstract Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. According to the Osmotic Engine Model, polarization of NHE1 at the leading edge of confined cells facilitates water uptake, cell protrusion and motility. The physiological relevance of the Osmotic Engine Model and the identity of molecules mediating cell rear shrinkage remain elusive. Here, we demonstrate that NHE1 and SWELL1 preferentially polarize at the cell leading and trailing edges, respectively, mediate cell volume regulation, cell dissemination from spheroids and confined migration. SWELL1 polarization confers migration direction and efficiency, as predicted mathematically and determined experimentally via optogenetic spatiotemporal regulation. Optogenetic RhoA activation at the cell front triggers SWELL1 re-distribution and migration direction reversal in SWELL1-expressing, but not SWELL1-knockdown, cells. Efficient cell reversal also requires Cdc42, which controls NHE1 repolarization. Dual NHE1/SWELL1 knockdown inhibits breast cancer cell extravasation and metastasis in vivo, thereby illustrating the physiological significance of the Osmotic Engine Model. 

Abstract Cells respond to physical stimuli, such as stiffness 1 , fluid shear stress 2 and hydraulic pressure 3,4 . Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer 5 . However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na + /H + exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology. 

Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.