Animal cell migration is predominantly driven by the coordinated, yet stochastic, polymerization of thousands of nanometer-scale actin filaments across micron-scale cell leading edges. It remains unclear how such inherently noisy processes generate robust cellular behavior. We employed high-speed imaging of migrating neutrophil-like HL-60 cells to explore the fine-scale shape fluctuations that emerge and relax throughout the process of leading edge maintenance. We then developed a minimal stochastic model of the leading edge that reproduces this stable relaxation behavior. Remarkably, we find lamellipodial stability naturally emerges from the interplay between branched actin network growth and leading edge shape - with no additional feedback required - based on a synergy between membrane-proximal branching and lateral spreading of filaments. These results thus demonstrate a novel biological noise-suppression mechanism based entirely on system geometry. Furthermore, our model suggests that the Arp2/3-mediated ~70‑80º branching angle optimally smooths lamellipodial shape, addressing its long-mysterious conservation from protists to mammals.
Analysis and modeling code for this paper is available on the Theriot lab Gitlab:<https://gitlab.com/theriot_lab/leading-edge-stability-in-motile-cells-is-an-emergent-property-of-branched-actin-network-growth> under the MIT license. Figure data are available in the Source Data files. The large size of the raw video microscopy data (865 GB of image files in the Open Microscopy Environment OME-TIFF format) and the associated analyzed data (320 GB) prohibits their upload to a public repository. The complete raw and analyzed data files for one example experimental dataset and one example simulated dataset (corresponding to the data shown in Fig. 1a-f and Fig. 2c-j, respectively) are available on Figshare <https://figshare.com/projects/Leading_edge_stability_in_motile_cells_is_an_emergent_property_of_branched_actin_network_growth/132878>. Code to analyze this data are publicly available on Gitlab as noted above. Requests for additional raw or analyzed data should be sent to the corresponding author by email. Data will be made available in the form of a hard drive shipped by mail. There are no restrictions on who may access the data.
- Rikki M Garner
- Julie A Theriot
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Experiments using zebrafish larvae were approved by the University of Washington Institutional Animal Care and Use Committee (protocol 4427-01).
- Alphee Michelot, Institut de Biologie du Développement, France
© 2022, Garner & Theriot
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.
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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