Consequences of PDGFR a + fibroblast reduction in adult murine hearts

  1. Jill T Kuwabara
  2. Akitoshi Hara
  3. Sumit Bhutada
  4. Greg S Gojanovich
  5. Jasmine Chen
  6. Kanani Hokutan
  7. Vikram Shettigar
  8. Anson Y Lee
  9. Lydia P DeAngelo
  10. Jack R Heckl
  11. Julia R Jahansooz
  12. Dillon K Tacdol
  13. Mark T Ziolo
  14. Suneel S Apte
  15. Michelle D Tallquist  Is a corresponding author
  1. University of Hawaii at Manoa, United States
  2. Cleveland Clinic Lerner Research Institute, United States
  3. The Ohio State University Wexner Medical Center, United States

Abstract

Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, a microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.

Data availability

Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD021741 (shotgun proteomics) and PXD021739 (N-terminomics).

The following data sets were generated

Article and author information

Author details

  1. Jill T Kuwabara

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Akitoshi Hara

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sumit Bhutada

    Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Greg S Gojanovich

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jasmine Chen

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kanani Hokutan

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Vikram Shettigar

    Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anson Y Lee

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lydia P DeAngelo

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0549-325X
  10. Jack R Heckl

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Julia R Jahansooz

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Dillon K Tacdol

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Mark T Ziolo

    Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Suneel S Apte

    Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8441-1226
  15. Michelle D Tallquist

    Center for Cardiovascular Research, University of Hawaii at Manoa, Honolulu, United States
    For correspondence
    michelle.tallquist@hawaii.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1383-144X

Funding

National Institutes of Health (HL074257)

  • Michelle D Tallquist

National Institutes of Health (HL115505)

  • Jill T Kuwabara

American Heart Association (PRE29630019)

  • Jill T Kuwabara

American Heart Association (GRNT33660474)

  • Michelle D Tallquist

American Heart Association (PRE834732)

  • Jasmine Chen

American Heart Association

  • Suneel S Apte

Paul G. Allen Frontiers Group

  • Suneel S Apte

Japan Society for the Promotion of Science

  • Akitoshi Hara

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

Ethics

Animal experimentation: All mouse experiments were performed according to the animal experimental guidelines issued and approved by Institutional Animal Care and Use Committees of the University of Hawaii at Manoa (APN12-1421 and APN12-1469) and The Ohio State University Wexner Medical Center (#2021A00000070). All surgeries were performed under isofluorane anesthesia, and every effort was made to minimize suffering.

Copyright

© 2022, Kuwabara 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. Jill T Kuwabara
  2. Akitoshi Hara
  3. Sumit Bhutada
  4. Greg S Gojanovich
  5. Jasmine Chen
  6. Kanani Hokutan
  7. Vikram Shettigar
  8. Anson Y Lee
  9. Lydia P DeAngelo
  10. Jack R Heckl
  11. Julia R Jahansooz
  12. Dillon K Tacdol
  13. Mark T Ziolo
  14. Suneel S Apte
  15. Michelle D Tallquist
(2022)
Consequences of PDGFR a + fibroblast reduction in adult murine hearts
eLife 11:e69854.
https://doi.org/10.7554/eLife.69854

Share this article

https://doi.org/10.7554/eLife.69854

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