Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Abstract

The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFβ and Notch signaling in this fate specification process, there is increasing evidence that liver progenitors are sensitive to mechanical cues. Here, we utilized microarrayed patterns to provide a controlled biochemical and biomechanical microenvironment for mouse liver progenitor cell differentiation. In these defined circular geometries, we observed biliary differentiation at the periphery and hepatocytic differentiation in the center. Parallel measurements obtained by traction force microscopy showed substantial stresses at the periphery, coincident with maximal biliary differentiation. We investigated the impact of downstream signaling, showing that peripheral biliary differentiation is dependent not only on Notch and TGFβ but also E-cadherin, myosin-mediated cell contractility, and ERK. We have therefore identified distinct combinations of microenvironmental cues which guide fate specification of mouse liver progenitors toward both hepatocyte and biliary fates.

Data availability

Source data tables (9 total) for the immunofluorescence and TFM array experiments have been attached to this submission and are associated with the relevant figures. Source code files (11 total) have been uploaded for the TFM analysis (Figure 4-6), FEM simulations (Figure 4), and Notch simulations (Figure 5). A detailed protocol for our array analysis technique together with source code has been made available elsewhere, see Kaylan et al. (J Vis Exp, 2017, e55362, http://dx.doi.org/10.3791/55362).

Article and author information

Author details

  1. Kerim B Kaylan

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7147-0614
  2. Ian C Berg

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew J Biehl

    Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Aidan Brougham-Cook

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ishita Jain

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sameed M Jamil

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lauren H Sargeant

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nicholas J Cornell

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lori T Raetzman

    Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gregory H Underhill

    Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, United States
    For correspondence
    gunderhi@illinois.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1002-5335

Funding

National Institute of Biomedical Imaging and Bioengineering (5R03EB022254-02)

  • Gregory H Underhill

National Science Foundation (1636175)

  • Gregory H Underhill

National Institute of Biomedical Imaging and Bioengineering (T32EB019944)

  • Ian C Berg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Reviewing Editor

  1. Gordana Vunjak-Novakovic, Columbia University, United States

Version history

  1. Received: May 21, 2018
  2. Accepted: December 24, 2018
  3. Accepted Manuscript published: December 27, 2018 (version 1)
  4. Version of Record published: January 22, 2019 (version 2)

Copyright

© 2018, Kaylan 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. Kerim B Kaylan
  2. Ian C Berg
  3. Matthew J Biehl
  4. Aidan Brougham-Cook
  5. Ishita Jain
  6. Sameed M Jamil
  7. Lauren H Sargeant
  8. Nicholas J Cornell
  9. Lori T Raetzman
  10. Gregory H Underhill
(2018)
Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling
eLife 7:e38536.
https://doi.org/10.7554/eLife.38536

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https://doi.org/10.7554/eLife.38536

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