Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity

  1. Su-Jin Heo
  2. Tristan P Driscoll
  3. Stephen D Thorpe
  4. Nandan L Nerurkar
  5. Brendon M Baker
  6. Michael T Yang
  7. Christopher S Chen
  8. David A Lee
  9. Robert L Mauck  Is a corresponding author
  1. Perelman School of Medicine, University of Pennsylvania, United States
  2. Queen Mary University of London, United Kingdom
  3. Harvard University, United States
  4. Boston University, United States

Abstract

Mesenchymal stem cell (MSC) differentiation is mediated by soluble and physical cues. In this study, we investigated differentiation induced transformations in MSC cellular and nuclear biophysical properties and queried their role in mechanosensation. Our data show that nuclei in differentiated bovine and human MSCs stiffen and become resistant to deformation. This attenuated nuclear deformation was governed by restructuring of Lamin A/C and increased heterochromatin content. This change in nuclear stiffness sensitized MSCs to mechanical loading induced calcium signaling and differentiated marker expression. This sensitization was reversed when the 'stiff' differentiated nucleus was softened, and was enhanced when the 'soft' undifferentiated nucleus was stiffened through pharmacologic treatment. Interestingly, dynamic loading of undifferentiated MSCs, in the absence of soluble differentiation factors, stiffened and condensed the nucleus, and increased mechanosensitivity more rapidly than soluble factors. These data suggest that the nucleus acts as a mechanostat to modulate cellular mechanosensation during differentiation.

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Author details

  1. Su-Jin Heo

    McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tristan P Driscoll

    McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Stephen D Thorpe

    Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4707-7756
  4. Nandan L Nerurkar

    Department of Genetics, Harvard Medical School, Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Brendon M Baker

    Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael T Yang

    Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christopher S Chen

    Department of Biomedical Engineering, College of Engineering, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. David A Lee

    Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Robert L Mauck

    McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    lemauck@mail.med.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9537-603X

Funding

National Institutes of Health

  • Su-Jin Heo
  • Tristan P Driscoll
  • Nandan L Nerurkar
  • Brendon M Baker
  • Michael T Yang
  • Christopher S Chen
  • Robert L Mauck

Human Frontiers in Science Program

  • Su-Jin Heo
  • Tristan P Driscoll
  • Stephen D Thorpe
  • David A Lee
  • Robert L Mauck

The Penn Center for Musculoskeletal Disorders

  • Su-Jin Heo
  • Tristan P Driscoll
  • Robert L Mauck

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

Reviewing Editor

  1. Todd McDevitt, Gladstone Institutes, United States

Publication history

  1. Received: June 3, 2016
  2. Accepted: November 29, 2016
  3. Accepted Manuscript published: November 30, 2016 (version 1)
  4. Version of Record published: December 9, 2016 (version 2)

Copyright

© 2016, Heo 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. Su-Jin Heo
  2. Tristan P Driscoll
  3. Stephen D Thorpe
  4. Nandan L Nerurkar
  5. Brendon M Baker
  6. Michael T Yang
  7. Christopher S Chen
  8. David A Lee
  9. Robert L Mauck
(2016)
Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity
eLife 5:e18207.
https://doi.org/10.7554/eLife.18207
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