Close

Tissue size controls patterns of cell proliferation and migration in freely-expanding epithelia

Matthew A. Heinrich, Julienne M. LaChance, Tom J. Zajdel, Ricard Alert, Andrej Košmrlj, Daniel J. Cohen

Posted on: 21 May 2020

Preprint posted on 28 February 2020

Article now published in eLife at http://dx.doi.org/10.7554/eLife.58945

Size matters - epithelial tissue size dictates proliferation and migration dynamics

Selected by Ilaria Di Meglio

BACKGROUND

Cell proliferation and migration control represents a critical aspect of tissue formation and maintenance in vivo. However, the exact mechanisms by which tissues coordinate cellular behaviour to give rise to the complexity of a living organism are not fully understood. Among the first descriptions of tissue size control was the concept of contact inhibition, a term first proposed over half a century ago [1], which refers to the inhibition of cell migration and eventually proliferation [2] due to extensive mutual contact between cells as density in a tissue increases. Since then, many in vitro studies have employed model epithelial tissues to elucidate the underlying mechanisms that drive migration and proliferation control [3-8]. However, as remarked by Heinrich et al, most studies have restricted tissue growth to the sub-millimetric scale (<500 microns) and have not assessed long-term growth (more than 24 hours), which may give rise to emergent complexity of the tissue. With this in mind, the authors investigate how tissue size affects the spreading and growth of a model MDCK epithelium grown on patterns of >1mm in diameter.

 

KEY FINDINGS

A model epithelial tissue of MDCK cells is grown on circular patterns of either small (1.7mm) or large (3.4mm) diameter with the same starting cell density, and allowed to freely expand for over 46h (Fig.1). A first characterization of tissue dynamics indicates a difference in growth and migration dynamics between small and large tissues; relative area increase is greater for small tissues compared to large tissues, whereas tissue density increases monotonically in large tissues but not in small tissues. This difference is attributed to the finding that in the early stages of expansion of small tissues, migration plays a stronger role than cell division in small tissues. By relating the dynamics of area expansion to kinematic measurements, the authors find that the average radial expansion of the tissue depends on the perimeter-to-area ratio of the pattern and not on tissue size, which could explain why smaller patterns exhibit faster area expansion compared to larger patterns.

Figure 1 – Expansion dynamics of small (left) and large (right) millimetric-size cell monolayers over 46h of growth (taken from Fig. 1 in Heinrich et al., 2020)

 

Next, the authors characterize the migratory behaviour and find that migration dynamics at the outer edge are independent of tissue size; speed is high and constant in both small and large tissues. In contrast, migratory dynamics within the bulk of the tissue are size-dependent. Towards the inner region of tissues, the speed profile diverges, and small tissues exhibit a motile interior region while large tissues exhibit an interior region that is almost completely non-motile past 28h of growth. As opposed to speed, the radial component of the velocity field is almost identical for small and large tissues, decreasing as distance from the tissue edge increases. Interestingly, the difference between radial velocity and speed observed for small tissues is due to the emergence of tissue-spanning, fast vortices in the centre small tissues (Fig.2). The formation of these vortices coincides temporally and spatially with a local cell density minimum occurring in small tissues. Using a minimal model that recapitulates the cell density evolution in small and large tissues, the observed transient decrease in density at the centre of small tissues is attributed to the combination of outward tissue flow and exponential growth of the tissue.

Figure 2 – Cell trajectories for small (left) and large (right) tissues illustrate vortex formation in expanding epithelia (taken from Fig. 3 in Heinrich et al., 2020)

 

Finally, the authors also analyze the spatiotemporal cell cycle dynamics in small and large tissues by using MDCK cells expressing FUCCI, meaning that cells fluoresce in red (shown as magenta) during G1-phase and in green when in the S-G2-M phase of the cell cycle. Similar to migration dynamics, cell cycle dynamics are independent of tissue size in the outer region of tissues, where cells are in the S-G2-M phases and thus are actively cycling. In contrast, the inner regions of small and large tissues exhibit different dynamics; large tissues are populated primarily by (contact-inhibited) G1-phase cells, while small tissues exhibit a mix of both G1 and S-G2-M phase cells where local density minimum and vortices occur. The contact-inhibited state observed in the centre of large tissues actually propagates inwards and does not originate from the core of the tissue (Fig. 3).

Figure 3 – Fluorescence images at the end of the experiment (46h) of G1 phase (magenta) and G2 phase (green) cells shows spatial cell-cycle dynamics in small (left) and large (right) tissues (taken from Fig.5 in Heinrich et al., 2020)

 

Altogether, the authors show that tissue size dictates the migratory and proliferative behaviour of the tissue. Importantly, edge dynamics are conserved across tissue size whereas dynamics at the bulk of the tissue are not. In fact, while a small tissue eventually reaches the size of a large tissue, its internal dynamics are different from the large tissue at this size. Therefore, initial tissue size alters the growth constraints under which the tissue grows and this ultimately determines the growth patterns within the bulk of the tissue.

 

Why I like this preprint:

I found this preprint particularly interesting because it focuses on assessing the effect of tissue size and growth on the dynamics of both migration and proliferation. With a few exceptions, most studies using cultured MDCK cells focus on one of the two processes, yet the control and dynamics of both are equally important in the context of a growing tissue. Even more so, migration and proliferation patterns are highly interlinked, highlighting the importance of assessing both in a growing tissue. I think this study is also particularly relevant because it explores tissue dynamics at the larger scale, and indeed in vivo tissues can extend for millimeters or even meters! Finally, I liked the use of the FUCCI system in this study because it allows one to assess the effect of mechanics and in this case of tissue size on local cell cycle progression and not only on overall proliferation rate.

 

Questions to the authors:

  • The authors use plastic culture dishes in this study, which are several orders of magnitude stiffer than tissues. I think it would be interesting to assess the same dynamics at the millimetric-scale as has been done here but on substrates that are of physiologically relevant stiffness, which may give rise to further complexity in the dynamics observed.
  • Do you observe cell extrusion and if so is there a difference between small and large tissues, and between edge and tissue core?
  • The effect of aspect ratio on tissue expansion, which you assess by growing elliptical shaped tissues of major to minor axis ratios 8:1 or 4:1, also appears to impact vortex formation. The formation of a vortex is very evident in the movie S3 for the 8:1 tissue but not the 4:1 tissue – what could be the explanation for this difference?

References

  1. Abercrombie, M. and J.E. Heaysman, Observations on the social behaviour of cells in tissue culture. II. Monolayering of fibroblasts. Exp Cell Res, 1954. 6(2): p. 293-306.
  2. Stoker, M.G. and H. Rubin, Density dependent inhibition of cell growth in culture. Nature, 1967. 215(5097): p. 171-2.
  3. Nelson, C.M., et al., Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci U S A, 2005. 102(33): p. 11594-9.
  4. Puliafito, A., et al., Collective and single cell behavior in epithelial contact inhibition. Proc Natl Acad Sci U S A, 2012. 109(3): p. 739-44.
  5. Streichan, S.J., et al., Spatial constraints control cell proliferation in tissues. Proc Natl Acad Sci U S A, 2014. 111(15): p. 5586-91.
  6. Uroz, M., et al., Regulation of cell cycle progression by cell-cell and cell-matrix forces. Nat Cell Biol, 2018. 20(6): p. 646-654.
  7. Vedula, S.R., et al., Emerging modes of collective cell migration induced by geometrical constraints. Proc Natl Acad Sci U S A, 2012. 109(32): p. 12974-9.
  8. Wyatt, T.P., et al., Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. Proc Natl Acad Sci U S A, 2015. 112(18): p. 5726-31

 

doi: https://doi.org/10.1242/prelights.20855

Read preprint (No Ratings Yet)

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the biophysics category:

Motor Clustering Enhances Kinesin-driven Vesicle Transport

Rui Jiang, Qingzhou Feng, Daguan Nong, et al.

Selected by 16 November 2024

Sharvari Pitke

Biophysics

Global coordination of protrusive forces in migrating immune cells

Patricia Reis-Rodrigues, Nikola Canigova, Mario J. Avellaneda, et al.

Selected by 10 October 2024

yohalie kalukula

Biophysics

Engineered Nanotopographies Induce Transient Openings in the Nuclear Membrane

Einollah Sarikhani, Vrund Patel, Zhi Li, et al.

Selected by 23 September 2024

Sristilekha Nath

Bioengineering

Also in the cell biology category:

Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder

Thomas Larrieu, Charline Carron, Fabio Grieco, et al.

Selected by 04 December 2024

Harvey Roweth

Neuroscience

Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates

Karen A Lindquist, Jennifer Mecklenburg, Anahit H. Hovhannisyan, et al.

Selected by 04 December 2024

Vanessa Ehlers

Neuroscience

Motor Clustering Enhances Kinesin-driven Vesicle Transport

Rui Jiang, Qingzhou Feng, Daguan Nong, et al.

Selected by 16 November 2024

Sharvari Pitke

Biophysics

Also in the developmental biology category:

Cellular signalling protrusions enable dynamic distant contacts in spinal cord neurogenesis

Joshua Hawley, Robert Lea, Veronica Biga, et al.

Selected by 15 November 2024

Ankita Walvekar

Developmental Biology

Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation

Marianne Basso, Alexia Mahuzier, Syed Kaabir Ali, et al.

Selected by 30 October 2024

Ryan Harrison

Developmental Biology

HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

Estefania Sanchez-Vasquez, Marianne E. Bronner, Magdalena Zernicka-Goetz

Selected by 11 October 2024

Anchel De Jaime Soguero

Developmental Biology

Also in the cell biology category:

November 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

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage

Also in the developmental biology category:

BSDB/GenSoc Spring Meeting 2024

A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.

 



List by Joyce Yu, Katherine Brown

GfE/ DSDB meeting 2024

This preList highlights the preprints discussed at the 2024 joint German and Dutch developmental biology societies meeting that took place in March 2024 in Osnabrück, Germany.

 



List by Joyce Yu

‘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.

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)

 



List by Nándor Lipták

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

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

Society for Developmental Biology 79th Annual Meeting

Preprints at SDB 2020

 



List by Irepan Salvador-Martinez, Martin Estermann

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

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

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.

EDBC Alicante 2019

Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.

 



List by Sergio Menchero 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

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve

Pattern formation during development

The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.

 



List by Alexa Sadier

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

 



List by Shikha Nayar
Close