Extracellular Hydraulic Resistance Enhances Cell Migration

Abstract

Cells migrating in vivo can encounter microenvironments with varying physical properties. One such physical variable is the viscosity of the fluid surrounding the cell. Increased fluid viscosity is expected to increase the hydraulic resistance experienced by the migrating cell and therefore decrease the cell speed. We demonstrate that contrary to this expected result, cells migrate faster in high viscosity media on 2D substrates. To reveal the molecular mechanism, we examined both actin dynamics and water dynamics driven by ion channel activity. Results show that cells increased in area in high viscosity and actomyosin dynamics remained similar, except that actin retrograde flow speed is reduced. Inhibiting ion channel fluxes in high viscosity media results in a large reduction in cell speed, suggesting that water flux contributes to the observed speed increase. Moreover, inhibiting actin-dependent vesicular trafficking that transports ion channels from the ER to the cell boundary changes ion channel spatial positioning and reduces cell speed in high viscosity media. Cells also displayed altered Ca2+-activity in high viscosity media, and when cytoplasmic Ca2+ is sequestered, cell speed reduction and altered ion channel positioning were observed. Taken together, we find that the cell cytoplasmic actin-phase and water-phase are coupled during cell migration in high viscosity media. Directional water fluxes are mediated by ion channels whose position depend on actin-based vesicular trafficking. There are no significant changes in ion channel total content in high viscosity, in agreement with physical modeling that also predicts the observed cell speedup in high viscosity environment.

Hydrogen, Bicarbonate, and Their Associated Exchangers in Cell Volume Regulation

“…Of note, the presence of NBC also increases the baseline cell volume due to the additional ions brought by the transporter. We speculate that in wet-lab experiments, 50% volume increase is not expected because although too much ouabain, an NKE inhibitor, will kill cells, a small amount of ouabain (e.g., up to 50 μM for MDA-MB-231) alone has not been found to cause cell lysis (Gould III et al, 2018 ; Maity et al, 2020 ). We will next analyze the role of NBC in this process.…”

“…For example, the activity of NHE1 can be modulated by Ca 2+ through TRPV4, determining pH-dependent actin polymerization, providing mechanical stability to delineate lamellipodia structure, and defining the efficiency of cell migration (Di Giusto et al, 2020 ). Ca 2+ also affects the structure and dynamics of the cytoskeleton (Oertner and Matus, 2005 ; Hepler, 2016 ; Zhao et al, 2019 ; Maity et al, 2020 ), which further impacts the distribution and function of ion channel (Levina et al, 1994 ; Steele and Fedida, 2014 ; Vallés et al, 2015 ). The dependence of ion channel activity on Ca 2+ and other biochemical signals provides additional regulatory mechanisms for cells to maintain ion homeostasis under environmental perturbation.…”

Multiple particle tracking (MPT) using PEGylated nanoparticles reveals heterogeneity within murine lymph nodes and between lymph nodes at different locations

“…We have found that viscosity in the T and B cell zones are similar, though viscosity in the B cell zones is slightly higher at 0.4 ± 0.1 Pa·s compared to 0.27 ± 0.06 Pa·s in the T cell zone ( Figure 2F ). Studies have suggested that cell speed increases in fluids with higher viscosity [40, 41]. Recent studies have found that T cell motility changes throughout the LN, and is potentially dependent on the region within which the T cell is found [42].…”