Elasto-Plastic Transition in Epithelial Folding
Posted on: 11 March 2024 , updated on: 17 March 2024
Preprint posted on 20 December 2023
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
- Collinet, C. & Lecuit, T. Programmed and self-organized flow of information during morphogenesis. Nat. Rev. Mol. Cell Biol. 22, 245–265 (2021).
- 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).
- 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).
- Molnar, K. & Labouesse, M. The plastic cell: mechanical deformation of cells and tissues. Open Biol. 11, 210006 (2021).
- Okuda, S. et al. Strain-triggered mechanical feedback in self-organizing optic-cup morphogenesis. Sci. Adv. 4, eaau1354 (2018).
- 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).
- 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).
doi: https://doi.org/10.1242/prelights.36757
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Germplasm stability in zebrafish requires maternal Tdrd6a and Tdrd6c
Justin Gutkowski
Leukocytes use endothelial membrane tunnels to extravasate the vasculature
Felipe Del Valle Batalla
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
preListscell biology category:
in theNovember in preprints – the CellBio edition
This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression
List by | Felipe Del Valle Batalla et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
List by | Dey Lab, Amanda Haage |