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.

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.

Metrics

  • 4,629
    views
  • 751
    downloads
  • 83
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.44153

Further reading

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Catherine Pfefferli, Anna Jaźwińska
    Insight

    Experiments on zebrafish show that the regeneration of the heart after an injury is supported by lymphatic vessels.

    1. Developmental Biology
    Bin Zhu, Rui Wei ... Pei Liang
    Research Article

    Wing dimorphism is a common phenomenon that plays key roles in the environmental adaptation of aphid; however, the signal transduction in response to environmental cues and the regulation mechanism related to this event remain unknown. Adenosine (A) to inosine (I) RNA editing is a post-transcriptional modification that extends transcriptome variety without altering the genome, playing essential roles in numerous biological and physiological processes. Here, we present a chromosome-level genome assembly of the rose-grain aphid Metopolophium dirhodum by using PacBio long HiFi reads and Hi-C technology. The final genome assembly for M. dirhodum is 447.8 Mb, with 98.50% of the assembled sequences anchored to nine chromosomes. The contig and scaffold N50 values are 7.82 and 37.54 Mb, respectively. A total of 18,003 protein-coding genes were predicted, of which 92.05% were functionally annotated. In addition, 11,678 A-to-I RNA-editing sites were systematically identified based on this assembled M. dirhodum genome, and two synonymous A-to-I RNA-editing sites on CYP18A1 were closely associated with transgenerational wing dimorphism induced by crowding. One of these A-to-I RNA-editing sites may prevent the binding of miR-3036-5p to CYP18A1, thus elevating CYP18A1 expression, decreasing 20E titer, and finally regulating the wing dimorphism of offspring. Meanwhile, crowding can also inhibit miR-3036-5p expression and further increase CYP18A1 abundance, resulting in winged offspring. These findings support that A-to-I RNA editing is a dynamic mechanism in the regulation of transgenerational wing dimorphism in aphids and would advance our understanding of the roles of RNA editing in environmental adaptability and phenotypic plasticity.