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The extracellular matrix protein agrin promotes heart regeneration in mice

Author

Listed:
  • Elad Bassat

    (Weizmann Institute of Science)

  • Yara Eid Mutlak

    (Faculty of Biology)

  • Alex Genzelinakh

    (Weizmann Institute of Science)

  • Ilya Y. Shadrin

    (Duke University)

  • Kfir Baruch Umansky

    (Weizmann Institute of Science)

  • Oren Yifa

    (Weizmann Institute of Science)

  • David Kain

    (Weizmann Institute of Science)

  • Dana Rajchman

    (Weizmann Institute of Science)

  • John Leach

    (Baylor College of Medicine and The Texas Heart Institute)

  • Daria Riabov Bassat

    (Weizmann Institute of Science)

  • Yael Udi

    (Weizmann Institute of Science)

  • Rachel Sarig

    (Weizmann Institute of Science)

  • Irit Sagi

    (Weizmann Institute of Science)

  • James F. Martin

    (Baylor College of Medicine and The Texas Heart Institute)

  • Nenad Bursac

    (Duke University)

  • Shenhav Cohen

    (Faculty of Biology)

  • Eldad Tzahor

    (Weizmann Institute of Science)

Abstract

The adult mammalian heart is non-regenerative owing to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only during the first week of life. Here we show that changes in the composition of the extracellular matrix during this week can affect cardiomyocyte growth and differentiation in mice. We identify agrin, a component of neonatal extracellular matrix, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant agrin promotes the division of cardiomyocytes that are derived from mouse and human induced pluripotent stem cells through a mechanism that involves the disassembly of the dystrophin–glycoprotein complex, and Yap- and ERK-mediated signalling. In vivo, a single administration of agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests that there are additional therapeutic mechanisms. Together, our results uncover a new inducer of mammalian heart regeneration and highlight fundamental roles of the extracellular matrix in cardiac repair.

Suggested Citation

  • Elad Bassat & Yara Eid Mutlak & Alex Genzelinakh & Ilya Y. Shadrin & Kfir Baruch Umansky & Oren Yifa & David Kain & Dana Rajchman & John Leach & Daria Riabov Bassat & Yael Udi & Rachel Sarig & Irit Sa, 2017. "The extracellular matrix protein agrin promotes heart regeneration in mice," Nature, Nature, vol. 547(7662), pages 179-184, July.
    • Handle: RePEc:nat:nature:v:547:y:2017:i:7662:d:10.1038_nature22978
    DOI: 10.1038/nature22978
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    Cited by:

    1. María García-García & Sara Sánchez-Perales & Patricia Jarabo & Enrique Calvo & Trevor Huyton & Liran Fu & Sheung Chun Ng & Laura Sotodosos-Alonso & Jesús Vázquez & Sergio Casas-Tintó & Dirk Görlich & , 2022. "Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Slobodan Vukicevic & Andrea Colliva & Vera Kufner & Valentina Martinelli & Silvia Moimas & Simone Vodret & Viktorija Rumenovic & Milan Milosevic & Boris Brkljacic & Diana Delic-Brkljacic & Ricardo Cor, 2022. "Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Ian Fernandes & Shunsuke Funakoshi & Homaira Hamidzada & Slava Epelman & Gordon Keller, 2023. "Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Wenya Ma & Yanan Tian & Leping Shi & Jing Liang & Qimeng Ouyang & Jianglong Li & Hongyang Chen & Hongyue Sun & Haoyu Ji & Xu Liu & Wei Huang & Xinlu Gao & Xiaoyan Jin & Xiuxiu Wang & Yining Liu & Yang, 2024. "N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Carmen Sena-Tomás & Angelika G. Aleman & Caitlin Ford & Akriti Varshney & Di Yao & Jamie K. Harrington & Leonor Saúde & Mirana Ramialison & Kimara L. Targoff, 2022. "Activation of Nkx2.5 transcriptional program is required for adult myocardial repair," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Sayan Chakraborty & Divyaleka Sampath & Melissa Ong Yu Lin & Matthew Bilton & Cheng-Kuang Huang & Mui Hoon Nai & Kizito Njah & Pierre-Alexis Goy & Cheng-Chun Wang & Ernesto Guccione & Chwee-Teck Lim &, 2021. "Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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