Cells use molecular working memory to navigate inchanging chemoattractant fields
Abstract
In order to migrate over large distances, cells within tissues and organisms rely on sensing local gradient cues which are irregular, conflicting, and changing over time and space. The mechanism how they generate persistent directional migration when signals are disrupted, while still remaining adaptive to signal's localization changes remain unknown. Here we find that single cells utilize a molecular mechanism akin to a working memory to satisfy these two opposing demands. We derive theoretically that this is characteristic for receptor networks maintained away from steady states. Time-resolved live-cell imaging of Epidermal growth factor receptor (EGFR) phosphorylation dynamics shows that cells transiently memorize position of encountered signals via slow-escaping remnant of the polarized signaling state, a dynamical 'ghost', driving memory-guided persistent directional migration. The metastability of this state further enables migrational adaptation when encountering new signals. We thus identify basic mechanism of real-time computations underlying cellular navigation in changing chemoattractant fields.
Data availability
Source data is provided with the submission. The numerical data used to generate the corresponding figures can be obtained from the codes deposited in https://github.com/akhileshpnn/Cell-memory.
Article and author information
Author details
Funding
Max Planck Society
- Aneta Koseska
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arvind Murugan, University of Chicago, United States
Version history
- Preprint posted: November 12, 2021 (view preprint)
- Received: January 6, 2022
- Accepted: June 3, 2022
- Accepted Manuscript published: June 6, 2022 (version 1)
- Version of Record published: July 14, 2022 (version 2)
Copyright
© 2022, Nandan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Cell Biology
- Physics of Living Systems
As cells migrate and experience forces from their surroundings, they constantly undergo mechanical deformations which reshape their plasma membrane (PM). To maintain homeostasis, cells need to detect and restore such changes, not only in terms of overall PM area and tension as previously described, but also in terms of local, nano-scale topography. Here we describe a novel phenomenon, by which cells sense and restore mechanically induced PM nano-scale deformations. We show that cell stretch and subsequent compression reshape the PM in a way that generates local membrane evaginations in the 100 nm scale. These evaginations are recognized by I-BAR proteins, which triggers a burst of actin polymerization mediated by Rac1 and Arp2/3. The actin polymerization burst subsequently re-flattens the evagination, completing the mechanochemical feedback loop. Our results demonstrate a new mechanosensing mechanism for PM shape homeostasis, with potential applicability in different physiological scenarios.
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- Cell Biology
- Physics of Living Systems
Cell-generated forces play a major role in coordinating the large-scale behavior of cell assemblies, in particular during development, wound healing, and cancer. Mechanical signals propagate faster than biochemical signals, but can have similar effects, especially in epithelial tissues with strong cell–cell adhesion. However, a quantitative description of the transmission chain from force generation in a sender cell, force propagation across cell–cell boundaries, and the concomitant response of receiver cells is missing. For a quantitative analysis of this important situation, here we propose a minimal model system of two epithelial cells on an H-pattern (‘cell doublet’). After optogenetically activating RhoA, a major regulator of cell contractility, in the sender cell, we measure the mechanical response of the receiver cell by traction force and monolayer stress microscopies. In general, we find that the receiver cells show an active response so that the cell doublet forms a coherent unit. However, force propagation and response of the receiver cell also strongly depend on the mechano-structural polarization in the cell assembly, which is controlled by cell–matrix adhesion to the adhesive micropattern. We find that the response of the receiver cell is stronger when the mechano-structural polarization axis is oriented perpendicular to the direction of force propagation, reminiscent of the Poisson effect in passive materials. We finally show that the same effects are at work in small tissues. Our work demonstrates that cellular organization and active mechanical response of a tissue are key to maintain signal strength and lead to the emergence of elasticity, which means that signals are not dissipated like in a viscous system, but can propagate over large distances.