Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration

Abstract

Zebrafish display a distinct ability to regenerate their heart following injury. However, this ability is not shared by another teleost, the medaka. In order to identify cellular and molecular bases for this difference, we performed comparative transcriptomic analyses following cardiac cryoinjury. This comparison points to major differences in immune cell dynamics between these models. Upon closer examination, we observed delayed and reduced macrophage recruitment in medaka, along with delayed neutrophil clearance. To investigate the role of immune responses in cardiac regeneration, we delayed macrophage recruitment in zebrafish and observed compromised neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. In contrast, stimulating Toll-like receptor signaling in medaka enhanced immune cell dynamics and promoted neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. Altogether, these data provide further insight into the complex role of the immune response during regeneration, and serve as a platform to identify and test additional regulators of cardiac repair.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Shih-Lei Lai

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    ben.s.lai@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1409-4701
  2. Rubén Marín-Juez

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  3. Pedro Luís Moura

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  4. Carsten Kuenne

    ECCPS Bioinformatics and deep sequencing platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  5. Jason Kuan Han Lai

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  6. Ayele Taddese Tsedeke

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

    ECCPS Bioinformatics and deep sequencing platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  8. Mario Looso

    ECCPS Bioinformatics and deep sequencing platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  9. Didier YR Stainier

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    Didier.Stainier@mpi-bn.mpg.de
    Competing interests
    Didier YR Stainier, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0382-0026

Funding

Max-Planck-Gesellschaft (Open-access funding)

  • Didier YR Stainier

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

Ethics

Animal experimentation: All zebrafish and medaka husbandry was performed under standard conditions, and all animal experiments were done in accordance with institutional (MPG) and national ethical and animal welfare guidelines approved by the ethics committee for animal experiments at the Regierungspräsidium Darmstadt, Germany (permit numbers B2-1023 and B2-1111).

Reviewing Editor

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

Publication history

  1. Received: January 30, 2017
  2. Accepted: June 15, 2017
  3. Accepted Manuscript published: June 20, 2017 (version 1)
  4. Accepted Manuscript updated: June 22, 2017 (version 2)
  5. Version of Record published: July 5, 2017 (version 3)

Copyright

© 2017, Stainier 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

  • 8,343
    Page views
  • 1,203
    Downloads
  • 159
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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. Shih-Lei Lai
  2. Rubén Marín-Juez
  3. Pedro Luís Moura
  4. Carsten Kuenne
  5. Jason Kuan Han Lai
  6. Ayele Taddese Tsedeke
  7. Stefan Guenther
  8. Mario Looso
  9. Didier YR Stainier
(2017)
Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration
eLife 6:e25605.
https://doi.org/10.7554/eLife.25605

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Hyun-Woo Jeong, Rodrigo Diéguez-Hurtado ... Ralf H Adams
    Tools and Resources

    The blood-brain barrier (BBB) limits the entry of leukocytes and potentially harmful substances from the circulation into the central nervous system (CNS). While BBB defects are a hallmark of many neurological disorders, the cellular heterogeneity at the neurovascular interface and the mechanisms governing neuroinflammation are not fully understood. Through single cell RNA sequencing of non-neuronal cell populations of the murine cerebral cortex during development, adulthood, ageing and neuroinflammation, we identify reactive endothelial venules (REVs), a compartment of specialised post-capillary endothelial cells (ECs) that are characterized by consistent expression of cell adhesion molecules, preferential leukocyte transmigration, association with perivascular macrophage populations, and endothelial activation initiating CNS immune responses. Our results provide novel insights into the heterogeneity of the cerebral vasculature and a useful resource for the molecular alterations associated with neuroinflammation and ageing.

    1. Developmental Biology
    Kazuaki Maruyama, Sachiko Miyagawa-Tomita ... Hiroki Kurihara
    Research Article

    Lymphatic vessels are crucial for tissue homeostasis and immune responses in vertebrates. Recent studies have demonstrated that lymphatic endothelial cells (LECs) arise from both venous sprouting (lymphangiogenesis) and de novo production from non-venous origins (lymphvasculogenesis), which is similar to blood vessel formation through angiogenesis and vasculogenesis. However, the contribution of LECs from non-venous origins to lymphatic networks is considered to be relatively small. Here, we identify the Islet1 (Isl1)-expressing cardiopharyngeal mesoderm (CPM) as a non-venous origin of craniofacial and cardiac LECs. Genetic lineage tracing with Isl1Cre/+ and Isl1CreERT2/+ mice suggested that a subset of CPM cells gives rise to LECs. These CPM-derived LECs are distinct from venous-derived LECs in terms of their developmental processes and anatomical locations. Later, they form the craniofacial and cardiac lymphatic vascular networks in collaboration with venous-derived LECs. Collectively, our results demonstrate that there are two major sources of LECs, the cardinal vein and the CPM. As the CPM is evolutionarily conserved, these findings may improve our understanding of the evolution of lymphatic vessel development across species. Most importantly, our findings may provide clues to the pathogenesis of lymphatic malformations, which most often develop in the craniofacial and mediastinal regions.