Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration

  1. Michael RM Harrison  Is a corresponding author
  2. Xidi Feng
  3. Guqin Mo
  4. Antonio Aguayo
  5. Jessi Villafuerte
  6. Tyler Yoshida
  7. Caroline A Pearson
  8. Stefan Schulte-Merker
  9. Ching-Ling Lien  Is a corresponding author
  1. Children's Hospital Los Angeles, United States
  2. University of California, Los Angeles, United States
  3. University of Münster, Germany

Abstract

The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that in cxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A significant defect in reducing the scar size after cryoinjury is observed in zebrafish with impaired Vegfc/Vegfr3 signaling that fail to develop intact cardiac lymphatic vessels. These results suggest that the cardiac lymphatic system can influence the regenerative potential of the myocardium.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 3, 4, 5 and 6

Article and author information

Author details

  1. Michael RM Harrison

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    For correspondence
    mharrison@chla.usc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1703-9879
  2. Xidi Feng

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Guqin Mo

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Antonio Aguayo

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jessi Villafuerte

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tyler Yoshida

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Caroline A Pearson

    Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Stefan Schulte-Merker

    Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3617-8807
  9. Ching-Ling Lien

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    For correspondence
    clien@chla.usc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5100-9780

Funding

National Heart, Lung, and Blood Institute (1R01HL130172)

  • Ching-Ling Lien

Children's Hospital Los Angeles (2nd R01 and Team Awards)

  • Ching-Ling Lien

American Heart Association (I81PA34180044)

  • Ching-Ling Lien

California Institute for Regenerative Medicine (EDUC2-08418)

  • Jessi Villafuerte

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

Ethics

Animal experimentation: Animal experimentation: All zebrafish husbandry was performed under standard conditions, and all animal experiments were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and following the ARRIVE guidelines provided by the National Centre for the Replacement, Refinement and Reduction of Animals in Research. All procedures were carried out as approved by the Children's Hospital Los Angeles (CHLA)institutional animal care and use committee (IACUC) protocols (#201-18 and 212-16).

Reviewing Editor

  1. Paul R Riley, University of Oxford, United Kingdom

Publication history

  1. Received: October 12, 2018
  2. Accepted: September 24, 2019
  3. Accepted Manuscript published: November 8, 2019 (version 1)
  4. Version of Record published: November 27, 2019 (version 2)

Copyright

© 2019, Harrison 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. Michael RM Harrison
  2. Xidi Feng
  3. Guqin Mo
  4. Antonio Aguayo
  5. Jessi Villafuerte
  6. Tyler Yoshida
  7. Caroline A Pearson
  8. Stefan Schulte-Merker
  9. Ching-Ling Lien
(2019)
Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration
eLife 8:e42762.
https://doi.org/10.7554/eLife.42762

Further reading

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