Abstract

The coordination of cell proliferation and migration in growing tissues is crucial in development and regeneration but remains poorly understood. Here, we find that, while expanding with an edge speed independent of initial conditions, millimeter-scale epithelial monolayers exhibit internal patterns of proliferation and migration that depend not on the current but on the initial tissue size, indicating memory effects. Specifically, the core of large tissues becomes very dense, almost quiescent, and ceases cell-cycle progression. In contrast, initially-smaller tissues develop a local minimum of cell density and a tissue-spanning vortex. To explain vortex formation, we propose an active polar fluid model with a feedback between cell polarization and tissue flow. Taken together, our findings suggest that expanding epithelia decouple their internal and edge regions, which enables robust expansion dynamics despite the presence of size and history-dependent patterns in the tissue interior.

Data availability

Representative raw datasets for each Figure are available at Zenodo DOI: 10.5281/zenodo.3858845Full raw dataset is hundreds of gigabytes due to the video data and can be provided upon request. Key analysis code provided at our github repository: Github DOI: 10.5281/zenodo.3861843

Article and author information

Author details

  1. Matthew A Heinrich

    Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ricard Alert

    Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1885-9177
  3. Julienne M LaChance

    Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tom J Zajdel

    Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrej Košmrlj

    Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6137-9200
  6. Daniel J Cohen

    Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, United States
    For correspondence
    danielcohen@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5819-1135

Funding

National Institutes of Health (1 R35GM133574-01)

  • Daniel J Cohen

Human Frontiers of Science Program (LT000475/2018-C)

  • Ricard Alert

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

Copyright

© 2020, Heinrich 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

  • 5,984
    views
  • 754
    downloads
  • 46
    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. Matthew A Heinrich
  2. Ricard Alert
  3. Julienne M LaChance
  4. Tom J Zajdel
  5. Andrej Košmrlj
  6. Daniel J Cohen
(2020)
Size-dependent patterns of cell proliferation and migration in freely-expanding epithelia
eLife 9:e58945.
https://doi.org/10.7554/eLife.58945

Share this article

https://doi.org/10.7554/eLife.58945

Further reading

    1. Developmental Biology
    Ming-Ming Chen, Yue Zhao ... Zheng-Xing Lian
    Research Article

    Mutations in the well-known Myostatin (MSTN) produce a ‘double-muscle’ phenotype, which makes it commercially invaluable for improving livestock meat production and providing high-quality protein for humans. However, mutations at different loci of the MSTN often produce a variety of different phenotypes. In the current study, we increased the delivery ratio of Cas9 mRNA to sgRNA from the traditional 1:2 to 1:10, which improves the efficiency of the homozygous mutation of biallelic gene. Here, a MSTNDel73C mutation with FGF5 knockout sheep, in which the MSTN and FGF5 dual-gene biallelic homozygous mutations were produced via the deletion of 3-base pairs of AGC in the third exon of MSTN, resulting in cysteine-depleted at amino acid position 73, and the FGF5 double allele mutation led to inactivation of FGF5 gene. The MSTNDel73C mutation with FGF5 knockout sheep highlights a dominant ‘double-muscle’ phenotype, which can be stably inherited. Both F0 and F1 generation mutants highlight the excellent trait of high-yield meat with a smaller cross-sectional area and higher number of muscle fibers per unit area. Mechanistically, the MSTNDel73C mutation with FGF5 knockout mediated the activation of FOSL1 via the MEK-ERK-FOSL1 axis. The activated FOSL1 promotes skeletal muscle satellite cell proliferation and inhibits myogenic differentiation by inhibiting the expression of MyoD1, and resulting in smaller myotubes. In addition, activated ERK1/2 may inhibit the secondary fusion of myotubes by Ca2+-dependent CaMKII activation pathway, leading to myoblasts fusion to form smaller myotubes.

    1. Computational and Systems Biology
    2. Developmental Biology
    Juan Manuel Gomez, Hendrik Nolte ... Maria Leptin
    Research Article Updated

    The initially homogeneous epithelium of the early Drosophila embryo differentiates into regional subpopulations with different behaviours and physical properties that are needed for morphogenesis. The factors at top of the genetic hierarchy that control these behaviours are known, but many of their targets are not. To understand how proteins work together to mediate differential cellular activities, we studied in an unbiased manner the proteomes and phosphoproteomes of the three main cell populations along the dorso-ventral axis during gastrulation using mutant embryos that represent the different populations. We detected 6111 protein groups and 6259 phosphosites of which 3398 and 3433 were differentially regulated, respectively. The changes in phosphosite abundance did not correlate with changes in host protein abundance, showing phosphorylation to be a regulatory step during gastrulation. Hierarchical clustering of protein groups and phosphosites identified clusters that contain known fate determinants such as Doc1, Sog, Snail, and Twist. The recovery of the appropriate known marker proteins in each of the different mutants we used validated the approach, but also revealed that two mutations that both interfere with the dorsal fate pathway, Toll10B and serpin27aex do this in very different manners. Diffused network analyses within each cluster point to microtubule components as one of the main groups of regulated proteins. Functional studies on the role of microtubules provide the proof of principle that microtubules have different functions in different domains along the DV axis of the embryo.