Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration

  1. Dana Gancz
  2. Brian C Raftrey
  3. Gal Perlmoter
  4. Rubén Marín-Juez
  5. Jonathan Semo
  6. Ryota L Matsuoka
  7. Ravi Karra
  8. Hila Raviv
  9. Noga Moshe
  10. Yoseph Addadi
  11. Ofra Golani
  12. Kenneth D Poss
  13. Kristy Red-Horse
  14. Didier Y Stainier
  15. Karina Yaniv  Is a corresponding author
  1. Weizmann Institute of Science, Israel
  2. Stanford University, United States
  3. Max Planck Institute for Heart and Lung Research, Germany
  4. Duke University, United States

Abstract

In recent years there has been increasing interest in the role of lymphatics in organ repair and regeneration, due to their importance in immune surveillance and fluid homeostasis. Experimental approaches aimed at boosting lymphangiogenesis following myocardial infarction in mice, were shown to promote healing of the heart. Yet, the mechanisms governing cardiac lymphatic growth remain unclear. Here we identify two distinct lymphatic populations in the hearts of zebrafish and mouse, one that forms through sprouting lymphangiogenesis, and the other by coalescence of isolated lymphatic cells. By tracing the development of each subset, we reveal diverse cellular origins and differential response to signaling cues. Finally, we show that lymphatic vessels are required for cardiac regeneration in zebrafish as mutants lacking lymphatics display severely impaired regeneration capabilities. Overall, our results provide novel insight into the mechanisms underlying lymphatic formation during development and regeneration, opening new avenues for interventions targeting specific lymphatic populations.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Dana Gancz

    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  2. Brian C Raftrey

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  3. Gal Perlmoter

    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  4. Rubén Marín-Juez

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  5. Jonathan Semo

    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  6. Ryota L Matsuoka

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  7. Ravi Karra

    Regeneration Next, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  8. Hila Raviv

    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  9. Noga Moshe

    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  10. Yoseph Addadi

    Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  11. Ofra Golani

    Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9793-236X
  12. Kenneth D Poss

    Regeneration Next, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  13. Kristy Red-Horse

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  14. Didier Y Stainier

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    Didier Y Stainier, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0382-0026
  15. Karina Yaniv

    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    Karina.Yaniv@weizmann.ac.il
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5638-7150

Funding

H2020 European Research Council (335605)

  • Karina Yaniv

National Institutes of Health (R01 HL131319)

  • Kenneth D Poss

National Institutes of Health (R01 136182)

  • Kenneth D Poss

American Heart Association

  • Kenneth D Poss

Fondation Leducq

  • Kenneth D Poss

United States-Israel Binational Science Foundation (2015289)

  • Karina Yaniv

Minerva Foundation (712610)

  • Karina Yaniv

H&M Kimmel Inst. for Stem cell research, the Estate of Emile Mimran

  • Karina Yaniv

National Institutes of Health (RO1-HL128503)

  • Kristy Red-Horse

New York Stem Cell Foundation

  • Kristy Red-Horse

Max-Planck-Gesellschaft

  • Didier Y Stainier

Fondation Leducq

  • Didier Y Stainier

National Institutes of Health (R01 HL081674)

  • Kenneth D Poss

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#01470218-2) of the Weizmann Institute of Science. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Weizmann Institute of Science. All surgery in fish was performed under tricaine anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: December 10, 2018
  2. Accepted: November 5, 2019
  3. Accepted Manuscript published: November 8, 2019 (version 1)
  4. Version of Record published: November 27, 2019 (version 2)
  5. Version of Record updated: December 4, 2019 (version 3)

Copyright

© 2019, Gancz 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. Dana Gancz
  2. Brian C Raftrey
  3. Gal Perlmoter
  4. Rubén Marín-Juez
  5. Jonathan Semo
  6. Ryota L Matsuoka
  7. Ravi Karra
  8. Hila Raviv
  9. Noga Moshe
  10. Yoseph Addadi
  11. Ofra Golani
  12. Kenneth D Poss
  13. Kristy Red-Horse
  14. Didier Y Stainier
  15. Karina Yaniv
(2019)
Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration
eLife 8:e44153.
https://doi.org/10.7554/eLife.44153

Further reading

    1. Developmental Biology
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    Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-ĸB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics affect migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established an injury model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. We conclude that successful fin bone regeneration appears to involve the coordinated execution of generic and regeneration-specific responses of osteoblasts to injury.