Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence

  1. Nicola Alessio
  2. Tiziana Squillaro
  3. Giovanni Di Bernardo
  4. Giovanni Galano
  5. Roberto De Rosa
  6. Mariarosa AB Melone
  7. Gianfranco Peluso
  8. Umberto Galderisi  Is a corresponding author
  1. Luigi Vanvitelli Campania University, Italy
  2. ASL Napoli 1, Italy
  3. National Research Council (CNR), Italy

Abstract

Senescent cells secrete several molecules, collectively named senescence-associated secretory phenotype (SASP). In the SASP of cells that became senescent following several in vitro chemical and physical stress, we identified the IGFBP-4 protein that can be considered a general stress mediator. This factor appeared to play a key role in senescence-paracrine signaling. We provided evidences showing that genotoxic injury, such as low dose irradiation, may promote an IGFBP-4 release in bloodstream both in mice irradiated with 100 mGy X-ray and in human subjects that received Computer Tomography. Increased level of circulating IGFBP-4 may be responsible of pro-aging effect. We found a significant increase of senescent cells in the lungs, heart, and kidneys of mice that were intraperitoneally injected with IGFBP-4 twice a week for two months. We then analyzed how genotoxic stressors may promote the release of IGFBP-4 and the molecular pathways associated with the induction of senescence by this protein.

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. Nicola Alessio

    Experimental Medicine, Luigi Vanvitelli Campania University, Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Tiziana Squillaro

    Experimental Medicine, Luigi Vanvitelli Campania University, Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Giovanni Di Bernardo

    Experimental Medicine, Luigi Vanvitelli Campania University, Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Giovanni Galano

    Centro P.S.I. Napoli Est - Barra, Naples, Italy, ASL Napoli 1, Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Roberto De Rosa

    Centro P.S.I. Napoli Est - Barra, Naples, Italy, ASL Napoli 1, Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Mariarosa AB Melone

    Medical, Surgical, Neurological, Metabolic Sciences, and Aging, Luigi Vanvitelli Campania University, Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Gianfranco Peluso

    Institute of Agri-Environmental Biology and Forestry (IBAF), National Research Council (CNR), Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Umberto Galderisi

    Experimental Medicine, Luigi Vanvitelli Campania University, Napoli, Italy
    For correspondence
    umberto.galderisi@unicampania.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0909-7403

Funding

Regione Campania (CUP B23D18000250007)

  • Umberto Galderisi

Regione Campania (CUP B23D18000250007)

  • Gianfranco Peluso

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

Ethics

Animal experimentation: The animals were handled in compliance with the protocols that were approved by the Animal Care and Use Committee of Luigi Vanvitelli Campania University. Italian Ministry of Health ethical approval n. 67/2012 A

Human subjects: Bone marrow aspirate samples were obtained from healthy donors (age 10-18 years) after informed consent. Campania Region Ethical Committee approval n. 317/2016 PR

Reviewing Editor

  1. Jean-Pierre Michel, University of Geneva, Switzerland

Publication history

  1. Received: December 17, 2019
  2. Accepted: March 29, 2020
  3. Accepted Manuscript published: March 30, 2020 (version 1)
  4. Version of Record published: April 6, 2020 (version 2)
  5. Version of Record updated: July 1, 2022 (version 3)

Copyright

© 2020, Alessio 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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  1. Nicola Alessio
  2. Tiziana Squillaro
  3. Giovanni Di Bernardo
  4. Giovanni Galano
  5. Roberto De Rosa
  6. Mariarosa AB Melone
  7. Gianfranco Peluso
  8. Umberto Galderisi
(2020)
Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence
eLife 9:e54523.
https://doi.org/10.7554/eLife.54523

Further reading

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    The spatiotemporal blood vessel formation and specification at the osteogenic and angiogenic interface of murine cranial bone defect repair were examined utilizing a high-resolution multiphoton-based imaging platform in conjunction with advanced optical techniques that allow interrogation of the oxygen microenvironment and cellular energy metabolism in living animals. Our study demonstrates the dynamic changes of vessel types, that is, arterial, venous, and capillary vessel networks at the superior and dura periosteum of cranial bone defect, suggesting a differential coupling of the vessel type with osteoblast expansion and bone tissue deposition/remodeling during repair. Employing transgenic reporter mouse models that label distinct types of vessels at the site of repair, we further show that oxygen distributions in capillary vessels at the healing site are heterogeneous as well as time- and location-dependent. The endothelial cells coupling to osteoblasts prefer glycolysis and are less sensitive to microenvironmental oxygen changes than osteoblasts. In comparison, osteoblasts utilize relatively more OxPhos and potentially consume more oxygen at the site of repair. Taken together, our study highlights the dynamics and functional significance of blood vessel types at the site of defect repair, opening up opportunities for further delineating the oxygen and metabolic microenvironment at the interface of bone tissue regeneration.