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Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction

Author

Listed:
  • Serena Zacchigna

    (International Centre for Genetic Engineering and Biotechnology (ICGEB)
    Azienda Sanitaria Universitaria Integrata di Trieste)

  • Valentina Martinelli

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Silvia Moimas

    (Azienda Sanitaria Universitaria Integrata di Trieste
    International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Andrea Colliva

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Marco Anzini

    (Azienda Sanitaria Universitaria Integrata di Trieste)

  • Andrea Nordio

    (Azienda Sanitaria Universitaria Integrata di Trieste)

  • Alessia Costa

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Michael Rehman

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Simone Vodret

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Cristina Pierro

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Giulia Colussi

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Lorena Zentilin

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Maria Ines Gutierrez

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Ellen Dirkx

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Carlin Long

    (International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Gianfranco Sinagra

    (Azienda Sanitaria Universitaria Integrata di Trieste)

  • David Klatzmann

    (Immunology-Immunopathology-Immunotherapy (i3)
    Clinical Investigation Center in Biotherapy and Inflammation-Immunopathology-Biotherapy Department (DHU i2B))

  • Mauro Giacca

    (Azienda Sanitaria Universitaria Integrata di Trieste
    International Centre for Genetic Engineering and Biotechnology (ICGEB))

Abstract

Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction.

Suggested Citation

  • Serena Zacchigna & Valentina Martinelli & Silvia Moimas & Andrea Colliva & Marco Anzini & Andrea Nordio & Alessia Costa & Michael Rehman & Simone Vodret & Cristina Pierro & Giulia Colussi & Lorena Zen, 2018. "Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04908-z
    DOI: 10.1038/s41467-018-04908-z
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    Cited by:

    1. Yasmin K. Alshoubaki & Bhavana Nayer & Yen-Zhen Lu & Ekaterina Salimova & Sin Nee Lau & Jean L. Tan & Daniela Amann-Zalcenstein & Peter F. Hickey & Gonzalo Monte-Nieto & Ajithkumar Vasanthakumar & Mik, 2024. "Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. João Cardeira-da-Silva & Qianchen Wang & Pooja Sagvekar & Janita Mintcheva & Stephan Latting & Stefan Günther & Radhan Ramadass & Michail Yekelchyk & Jens Preussner & Mario Looso & Jan Philipp Junker , 2024. "Antigen presentation plays positive roles in the regenerative response to cardiac injury in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Di Wu & Haomin Li & Mingwei Liu & Jun Qin & Yi Sun, 2022. "The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Siyuan Fu & Zhiyu Wang & Peihong Huang & Guanjun Li & Jian Niu & Zhiyang Li & Guangyue Zu & Pengcheng Zhou & Lianhui Wang & David Tai Leong & Xianguang Ding, 2025. "Programmable production of bioactive extracellular vesicles in vivo to treat myocardial infarction," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    5. Hung-Chih Chen & Yen-Wen Liu & Kuan-Cheng Chang & Yen-Wen Wu & Yi-Ming Chen & Yu-Kai Chao & Min-Yi You & David J. Lundy & Chen-Ju Lin & Marvin L. Hsieh & Yu-Che Cheng & Ray P. Prajnamitra & Po-Ju Lin , 2023. "Gut butyrate-producers confer post-infarction cardiac protection," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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