Force propagation between epithelial cells depends on active coupling and mechano-structural polarization

Abstract

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 shows an active response so that the cell doublet forms a coherent unit. However, force propagation and response of the receiver cell also strongly depends 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 is key to maintain signal strength and leads to the emergence of elasticity, which means that signals are not dissipated like in a viscous system, but can propagate over large distances.

Data availability

All data has been deposited on dryad (https://doi.org/10.5061/dryad.sj3tx9683). All code has been deposited on Github (https://github.com/ArturRuppel/ForceTransmissionInDoublets).

The following data sets were generated

Article and author information

Author details

  1. Artur Ruppel

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Dennis Wörthmüller

    Institute for Theoretical Physics, Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Vladimir Misiak

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6637-8071
  4. Manasi Kelkar

    London Centre for Nanotechnology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Irène Wang

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Philippe Moreau

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Adrien Méry

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9582-0519
  8. Jean Révilloud

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Guillaume Charras

    Department of Cell and Developmental Biology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7902-0279
  10. Giovanni Cappello

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5012-367X
  11. Thomas Boudou

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Ulrich Sebastian Schwarz

    Institute for Theoretical Physics, Heidelberg University, Heidelberg, Germany
    For correspondence
    schwarz@thphys.uni-heidelberg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1483-640X
  13. Martial Balland

    Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, Saint Martin d'Hères, France
    For correspondence
    martial.balland@univ-grenoble-alpes.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6585-9735

Funding

Swiss National Science Foundation (P2LAP3 164919)

  • Manasi Kelkar

European Research Council (CoG-647186)

  • Guillaume Charras

Agence Nationale de la Recherche (ANR-19-CE13-0028)

  • Giovanni Cappello

Centre National de la Recherche Scientifique

  • Thomas Boudou

Deutsche Forschungsgemeinschaft (SCHW 834/2-1)

  • Ulrich Sebastian Schwarz

Agence Nationale de la Recherche (ANR-17-CE30-0032-01)

  • Martial Balland

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Ruppel 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.

Metrics

  • 2,834
    views
  • 363
    downloads
  • 13
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Artur Ruppel
  2. Dennis Wörthmüller
  3. Vladimir Misiak
  4. Manasi Kelkar
  5. Irène Wang
  6. Philippe Moreau
  7. Adrien Méry
  8. Jean Révilloud
  9. Guillaume Charras
  10. Giovanni Cappello
  11. Thomas Boudou
  12. Ulrich Sebastian Schwarz
  13. Martial Balland
(2023)
Force propagation between epithelial cells depends on active coupling and mechano-structural polarization
eLife 12:e83588.
https://doi.org/10.7554/eLife.83588

Share this article

https://doi.org/10.7554/eLife.83588

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

    1. Cell Biology
    Affiong Ika Oqua, Kin Chao ... Alejandra Tomas
    Research Article

    G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.