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Elasto-Plastic Transition in Epithelial Folding

Aki Teranishi, Misato Mori, Rihoko Ichiki, Satoshi Toda, Go Shioi, Satoru Okuda

Posted on: 11 March 2024 , updated on: 17 March 2024

Preprint posted on 20 December 2023

A different origami-guide: Irreversible folds in morphogenesis

Selected by Teodora Piskova

Categories: cell biology

Introduction

Morphogenesis is the fascinating process of embryo and organ formation. It is orchestrated by both biochemical and mechanical interactions which are precisely controlled at multiple time and length scales1. The establishment of a certain three-dimensional structure requires tissue folding – a fundamental process which needs to be irreversible2. Tissue folding is often driven by epithelial sheets experiencing mechanical force instability, for example, apical constriction3. While certain advances have been made in understanding the driving forces of tissue folding, still little is known about the mechanical response of the tissue to those forces and its contribution to folding irreversibility. Upon deformation, biological tissues can either return to their original shape (‘elastic’ response) or maintain the deformation (‘plastic’ response)4. Previous work revealed that a ‘plastic’ response in the retinal pigment epithelium maintains deformation during optic-cup morphogenesis5. This preprint by Teranishi and colleagues uncovers, in great detail, the time constraints and molecular mechanisms behind the transition from an ‘elastic’ to ‘plastic’ response in an epithelium under deformation which establishes irreversible folding.

Key findings

Irreversible folding requires an elastoplastic transition

To evaluate bending plasticity, or the property to retain deformations, the authors designed an assay in which they used a glass pipette to indent into 3D tissue structures for different hold durations. Upon removal of the pipette, they assessed the shape of the tissue – did it return to its original shape exhibiting an elastic response) or did it maintain the deformation in a plastic response). Mouse embryonic optic vesicle tissue and organoids, as well as MDCK cysts, showed either an elastic or plastic response depending on the hold duration: At short hold durations below 30 min, the tissue recovered to its original shape, while longer hold durations resulted in irreversible deformations. Using MDCK cysts, the authors demonstrated that bending plasticity increases with hold duration in a non-linear fashion – surpassing a threshold duration induced a switch-like transition from an elastic to plastic response (= the ‘elastoplastic‘ transition).

Folding mechanically activates EGFR signaling

The preprint then focuses on understanding the molecular mechanism and pathways involved in deformation sensing. Since previous studies have demonstrated that mechanical forces and properties of the environment can activate epidermal growth factor receptor (EGFR) signaling in different contexts6,7, the authors examined its involvement in the elastoplastic response in their assay by pharmacological inhibition. Blocking EGFR abolished the elastoplastic response, and so did blocking one of its main downstream pathways: the phosphoinositide-3 kinase (PI3K)/Akt pathway. Interfering with the other main EGFR-activated pathway – the extracellular signal-related kinase (ERK) pathway – did not affect the elastoplastic response, despite short-term ERK activation near the folds evidenced by Förster resonance energy transfer (FRET) measurements. Looking upstream of EGFR activation, knock-outs of either all endogenous EGFR ligands or of EGF alone did not affect the elastoplastic transition in the cysts, pointing to a ligand-free mode of receptor activation.

EGFR signaling leads to calcium activity necessary for the elastoplastic transition

The preprint goes on to reveal the involvement of cation channels in the mechanosensing of the induced deformation. By blocking TRPC(1/6), TRPC1, TRPC6 and TRPC5 and by chelation of intracellular calcium, the authors could demonstrate that calcium signaling via TRPC6 and TRPC3 is necessary for the elastoplastic transition. Calcium imaging during the indentation assay of MDCK cysts showed calcium transients along the apicobasal axis of cells located at the fold. Blocking EGFR activation abolished calcium transients during the indentation, while EGFR activation was independent of the activity of mechanosensitive channels. These two mechanisms eventually come together: ligand-free EGFR activation leads to calcium activity which senses the fold and is necessary for the elastoplastic transition.

Actin bracket at the fold establishes the elastoplastic transition

Besides uncovering the deformation-sensing mechanism, the authors were interested in finding out how the elastoplastic transition is mechanistically established in terms of cellular composition and cytoskeletal organization. Live imaging of F-actin showed the formation of an actin bracket-like structure at the apical side and along the lateral sides of cells at the fold. The actin-bracket spans the area where the elevated calcium transients were observed. Timewise, bracket formation started at the point of highest folding and reached its complete degree of crosslinking within the critical duration of the transition. Inhibiting actin polymerization prevented bracket formation and the elastoplastic transition, while enhancing it accelerated the plastic deformation, indicating how crucial this structure is for establishing the irreversibility of the fold. Finally, the authors were able to demonstrate that actin bracket formation is dependent of the EGFR/PI3K/Akt pathway.

What I like about this preprint

I like that this preprint seeks to explain how certain material behaviors of tissues matter for fundamental processes such as morphogenesis and how it comes about in terms of molecular mechanism. The scientific community has been gaining powerful insights into the biomechanics of tissues and cells, using more and more powerful methods, but what always fascinates me is to see where a biomechanical feature is important and what mechanisms establish and control this behavior. Lastly, I am particularly interested in the mechanical behavior of epithelia and how it can shape the functions of these resilient and versatile tissues.

Questions for the authors

Besides the actin bracket formation, have you observed how other cytoskeletal elements rearrange at and around the fold? Once established, can you reverse the actin bracket by enhancing actin depolymerization after the critical duration time? Or do intermediate filaments and microtubules remodel to stabilize the fold?

When you indent, how does the sealed lumen of the cysts handle the pressure change? Is there some drainage? In particular, could there be a hydraulic pressure gradient contributing to the structural changes observed as with the actin bracket formation?

You showed activation of ERK downstream of EGFR. However, this pathway seems not to be important for the elastoplastic transition. Could you speculate on the possible role of ERK activity during folding in the broader context of morphogenesis?

References

  1. Collinet, C. & Lecuit, T. Programmed and self-organized flow of information during morphogenesis. Nat. Rev. Mol. Cell Biol. 22, 245–265 (2021).
  2. Haas, P. A., Höhn, S. S. M. H., Honerkamp-Smith, A. R., Kirkegaard, J. B. & Goldstein, R. E. The noisy basis of morphogenesis: Mechanisms and mechanics of cell sheet folding inferred from developmental variability. PLoS Biol. 16, e2005536 (2018).
  3. Matsuda, M., Rozman, J., Ostvar, S., Kasza, K. E. & Sokol, S. Y. Mechanical control of neural plate folding by apical domain alteration. Nat. Commun. 14, 8475 (2023).
  4. Molnar, K. & Labouesse, M. The plastic cell: mechanical deformation of cells and tissues. Open Biol. 11, 210006 (2021).
  5. Okuda, S. et al. Strain-triggered mechanical feedback in self-organizing optic-cup morphogenesis. Sci. Adv. 4, eaau1354 (2018).
  6. Lambert, S., Vind-Kezunovic, D., Karvinen, S. & Gniadecki, R. Ligand-Independent Activation of the EGFR by Lipid Raft Disruption. J. Investig. Dermatol. 126, 954–962 (2006).
  7. Umesh, V., Rape, A. D., Ulrich, T. A. & Kumar, S. Microenvironmental Stiffness Enhances Glioma Cell Proliferation by Stimulating Epidermal Growth Factor Receptor Signaling. PLoS ONE 9, e101771 (2014).

 

Tags: biomechanics, development, epithelium, mechanobiology, mechanosensing

doi: https://doi.org/10.1242/prelights.36757

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