Excitable dynamics in a molecularly-explicit model of cell motility: Mixed-mode oscillations and beyond

Plazen, Lucie; Khadra, Anmar

doi:10.1016/j.jtbi.2023.111450

Cited by 2 publications

(1 citation statement)

References 54 publications

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“…This can also help to reduce a large and complicated model into a hierarchy of submodels operating at fast, medium, and slow timescales. Each can be analyzed in turn in a more complete way, for example, see Keener and Sneyd, 2009 ; Desroches et al, 2022 ; Tran et al, 2009 ; Newby and Bressloff, 2010 ; Plazen et al, 2023 ; Plazen and Khadra, 2023 . Rescaling can also identify submodels or processes that are governed by a ‘small (dimensionless) parameter’ (e.g., ratios of rates of diffusion of the membrane-bound and cytosolic forms of regulatory proteins).…”

Section: Mathematical Modeling Approachesmentioning

confidence: 99%

From actin waves to mechanism and back: How theory aids biological understanding

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Edelstein‐Keshet

Gov

et al. 2023

eLife

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Actin dynamics in cell motility, division, and phagocytosis is regulated by complex factors with multiple feedback loops, often leading to emergent dynamic patterns in the form of propagating waves of actin polymerization activity that are poorly understood. Many in the actin wave community have attempted to discern the underlying mechanisms using experiments and/or mathematical models and theory. Here, we survey methods and hypotheses for actin waves based on signaling networks, mechano-chemical effects, and transport characteristics, with examples drawn from Dictyostelium discoideum, human neutrophils, Caenorhabditis elegans, and Xenopus laevis oocytes. While experimentalists focus on the details of molecular components, theorists pose a central question of universality: Are there generic, model-independent, underlying principles, or just boundless cell-specific details? We argue that mathematical methods are equally important for understanding the emergence, evolution, and persistence of actin waves and conclude with a few challenges for future studies.

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Section: Mathematical Modeling Approachesmentioning

confidence: 99%

From actin waves to mechanism and back: How theory aids biological understanding

Beta

Edelstein‐Keshet

Gov

et al. 2023

eLife

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Polarity and mixed-mode oscillations may underlie different patterns of cellular migration

Plazen

Rahbani

Brown

et al. 2023

Sci Rep

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In mesenchymal cell motility, several migration patterns have been observed, including directional, exploratory and stationary. Two key members of the Rho-family of GTPases, Rac and Rho, along with an adaptor protein called paxillin, have been particularly implicated in the formation of such migration patterns and in regulating adhesion dynamics. Together, they form a key regulatory network that involves the mutual inhibition exerted by Rac and Rho on each other and the promotion of Rac activation by phosphorylated paxillin. Although this interaction is sufficient in generating wave-pinning that underscores cellular polarization comprised of cellular front (high active Rac) and back (high active Rho), it remains unclear how they interact collectively to induce other modes of migration detected in Chinese hamster Ovary (CHO-K1) cells. We previously developed a six-variable (6V) reaction–diffusion model describing the interactions of these three proteins (in their active/phosphorylated and inactive/unphosphorylated forms) along with other auxiliary proteins, to decipher their role in generating wave-pinning. In this study, we explored, through computational modeling and image analysis, how differences in timescales within this molecular network can potentially produce the migration patterns in CHO-K1 cells and how switching between migration modes could occur. To do so, the 6V model was reduced to an excitable 4V spatiotemporal model possessing three different timescales. The model produced not only wave-pinning in the presence of diffusion, but also mixed-mode oscillations (MMOs) and relaxation oscillations (ROs). Implementing the model using the Cellular Potts Model (CPM) produced outcomes in which protrusions in the cell membrane changed Rac–Rho localization, resulting in membrane oscillations and fast directionality variations similar to those observed experimentally in CHO-K1 cells. The latter was assessed by comparing the migration patterns of experimental with CPM cells using four metrics: instantaneous cell speed, exponent of mean-square displacement ($$\alpha$$ α -value), directionality ratio and protrusion rate. Variations in migration patterns induced by mutating paxillin’s serine 273 residue were also captured by the model and detected by a machine classifier, revealing that this mutation alters the dynamics of the system from MMOs to ROs or nonoscillatory behaviour through variation in the scaled concentration of an active form of an adhesion protein called p21-Activated Kinase 1 (PAK). These results thus suggest that MMOs and adhesion dynamics are the key mechanisms regulating CHO-K1 cell motility.

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Excitable dynamics in a molecularly-explicit model of cell motility: Mixed-mode oscillations and beyond

Cited by 2 publications

References 54 publications

From actin waves to mechanism and back: How theory aids biological understanding

From actin waves to mechanism and back: How theory aids biological understanding

Polarity and mixed-mode oscillations may underlie different patterns of cellular migration

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