Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies

  1. Jesse D Rogers
  2. William James Richardson  Is a corresponding author
  1. Clemson University, United States

Abstract

Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex interactions between signaling pathways confounds efforts to develop therapies for regional scar formation. We employed a logic-based ordinary differential equation model of fibroblast mechano-chemo signal transduction to predict matrix protein expression in response to canonical biochemical stimuli and mechanical tension. Functional analysis of mechano-chemo interactions showed extensive pathway crosstalk with tension amplifying, dampening, or reversing responses to biochemical stimuli. Comprehensive drug target screens identified 13 mechano-adaptive therapies that promote matrix accumulation in regions where it is needed and reduce matrix levels in regions where it is not needed. Our predictions suggest that mechano-chemo interactions likely mediate cell behavior across many tissues and demonstrate the utility of multi-pathway signaling networks in discovering therapies for context-specific disease states.

Data availability

Our model, datasets used for analysis, and scripts necessary to reproduce all analysis and figures are freely available on GitHub ... https://github.com/SysMechBioLab/Fibroblast_Signaling_Network_Model.

The following data sets were generated

Article and author information

Author details

  1. Jesse D Rogers

    Department of Bioengineering, Clemson University, Clemson, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. William James Richardson

    Department of Bioengineering, Clemson University, Clemson, United States
    For correspondence
    wricha4@clemson.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8678-9716

Funding

National Institute of General Medical Sciences (GM121342)

  • William James Richardson

National Heart, Lung, and Blood Institute (HL144927)

  • William James Richardson

American Heart Association (17SDG33410658)

  • William James Richardson

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

Reviewing Editor

  1. Jennifer Flegg, The University of Melbourne, Australia

Version history

  1. Preprint posted: August 14, 2020 (view preprint)
  2. Received: September 6, 2020
  3. Accepted: February 8, 2022
  4. Accepted Manuscript published: February 9, 2022 (version 1)
  5. Version of Record published: February 16, 2022 (version 2)

Copyright

© 2022, Rogers & Richardson

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. Jesse D Rogers
  2. William James Richardson
(2022)
Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
eLife 11:e62856.
https://doi.org/10.7554/eLife.62856

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https://doi.org/10.7554/eLife.62856

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