Mechanical force regulates tendon extracellular matrix organization and tenocyte morphogenesis through TGFbeta signaling

  1. Arul Subramanian
  2. Lauren Fallon Kanzaki
  3. Jenna Lauren Galloway
  4. Thomas F Schilling  Is a corresponding author
  1. University of California, Irvine, United States
  2. Massachusetts General Hospital, United States

Abstract

Mechanical forces between cells and extracellular matrix (ECM) influence cell shape and function. Tendons are ECM-rich tissues connecting muscles with bones that bear extreme tensional force. Analysis of transgenic zebrafish expressing mCherry driven by the tendon determinant scleraxis reveals that tendon fibroblasts (tenocytes) extend arrays of microtubule-rich projections at the onset of muscle contraction. In the trunk, these form a dense curtain along the myotendinous junctions at somite boundaries, perpendicular to myofibers, suggesting a role as force sensors to control ECM production and tendon strength. Paralysis or destabilization of microtubules reduces projection length and surrounding ECM, both of which are rescued by muscle stimulation. Paralysis also reduces SMAD3 phosphorylation in tenocytes and chemical inhibition of TGFβ signaling shortens tenocyte projections. These results suggest that TGFβ, released in response to force, acts on tenocytes to alter their morphology and ECM production, revealing a feedback mechanism by which tendons adapt to tension.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Arul Subramanian

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8455-6804
  2. Lauren Fallon Kanzaki

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9564-2385
  3. Jenna Lauren Galloway

    Center for Regenerative Medicine, Harvard Stem Cell Institute, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Thomas F Schilling

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    For correspondence
    tschilli@uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1798-8695

Funding

National Institutes of Health (R01 AR67797)

  • Thomas F Schilling

National Institutes of Health (R01 DE013828)

  • Thomas F Schilling

National Institutes of Health (R21 AR62792)

  • Thomas F Schilling

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2000-2149) of the University of California, Irvine. Embryos were anesthetized with tricaine before stimulation assays.

Reviewing Editor

  1. Deborah Yelon, University of California, San Diego, United States

Publication history

  1. Received: May 4, 2018
  2. Accepted: November 26, 2018
  3. Accepted Manuscript published: November 26, 2018 (version 1)
  4. Version of Record published: January 24, 2019 (version 2)

Copyright

© 2018, Subramanian 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.

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  1. Arul Subramanian
  2. Lauren Fallon Kanzaki
  3. Jenna Lauren Galloway
  4. Thomas F Schilling
(2018)
Mechanical force regulates tendon extracellular matrix organization and tenocyte morphogenesis through TGFbeta signaling
eLife 7:e38069.
https://doi.org/10.7554/eLife.38069
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