1. Developmental Biology
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Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling

  1. Hua Shen
  2. Peiheng Gan
  3. Kristy Wang
  4. Ali Darehzereshki
  5. Kai Wang
  6. S Ram Kumar
  7. Ching-Ling Lien
  8. Michaela Patterson
  9. Ge Tao
  10. Henry Sucov  Is a corresponding author
  1. University of Southern California, United States
  2. Medical University of South Carolina, United States
  3. Children's Hospital Los Angeles, United States
  4. First Affiliated Hospital of Guangzhou Medical University, China
  5. Medical College of Wisconsin, United States
Research Article
  • Cited 9
  • Views 1,708
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Cite this article as: eLife 2020;9:e53071 doi: 10.7554/eLife.53071

Abstract

Injury to the newborn mouse heart is efficiently regenerated, but this capacity is lost by one week after birth. We found that IGF2, an important mitogen in heart development, is required for neonatal heart regeneration. IGF2 originates from the endocardium/endothelium and is transduced in cardiomyocytes by the insulin receptor. Following injury on postnatal day 1, absence of IGF2 abolished injury-induced cell cycle entry during the early part of the first postnatal week. Consequently, regeneration failed despite the later presence of additional cell cycle-inducing activities 7 days following injury. Most cardiomyocytes transition from mononuclear diploid to polyploid during the first postnatal week. Regeneration was rescued in Igf2-deficient neonates in three different contexts that elevate the percentage of mononuclear diploid cardiomyocytes beyond postnatal day 7. Thus, IGF2 is a paracrine-acting mitogen for heart regeneration during the early postnatal period, and IGF2-deficiency unmasks the dependence of this process on proliferation-competent mononuclear diploid cardiomyocytes.

Data availability

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

Article and author information

Author details

  1. Hua Shen

    Stem Cell Biology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Peiheng Gan

    Regenerative Medicine, Medical University of South Carolina, Charleston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kristy Wang

    Regenerative Medicine, Medical University of South Carolina, Charleston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ali Darehzereshki

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

    Cardiovascular Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. S Ram Kumar

    Surgery, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ching-Ling Lien

    Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5100-9780
  8. Michaela Patterson

    Cell Biology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3805-4181
  9. Ge Tao

    Regenerative Medicine, Medical University of South Carolina, Charleston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Henry Sucov

    Regenerative Medicine, Cardiology, Medical University of South Carolina, Charleston, United States
    For correspondence
    sucov@musc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3792-3795

Funding

National Institutes of Health (HL070123)

  • Henry Sucov

American Heart Association (17SDG33400141)

  • Ge Tao

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) protocol 10173 of the University of Southern California and protocols 2018-00642 and 2018-00310 of the Medical University of South Carolina.

Reviewing Editor

  1. Caroline E Burns, Boston Children's Hospital, United States

Publication history

  1. Received: October 28, 2019
  2. Accepted: March 12, 2020
  3. Accepted Manuscript published: March 13, 2020 (version 1)
  4. Version of Record published: March 30, 2020 (version 2)

Copyright

© 2020, Shen 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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