Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence
- Luigi Vanvitelli Campania University, Italy
- ASL Napoli 1, Italy
- 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
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.
Reviewing Editor
- Jean-Pierre Michel, University of Geneva, Switzerland
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
Version history
- Received: December 17, 2019
- Accepted: March 29, 2020
- Accepted Manuscript published: March 30, 2020 (version 1)
- Version of Record published: April 6, 2020 (version 2)
- 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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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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- Cell Biology
- Stem Cells and Regenerative Medicine
Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from Cd47−/− mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in Cd47−/− spleens but significantly depleted in Thbs1−/− spleens. Single-cell transcriptome and flow cytometry analyses indicated that loss of CD47 is associated with accumulation and increased proliferation in spleen of Ter119−CD34+ progenitors and Ter119+CD34− committed erythroid progenitors with elevated mRNA expression of Kit, Ermap, and Tfrc. Induction of committed erythroid precursors is consistent with the known function of CD47 to limit the phagocytic removal of aged erythrocytes. Conversely, loss of thrombospondin-1 delays the turnover of aged red blood cells, which may account for the suppression of committed erythroid precursors in Thbs1−/− spleens relative to basal levels in wild-type mice. In addition to defining a role for CD47 to limit extramedullary erythropoiesis, these studies reveal a thrombospondin-1-dependent basal level of extramedullary erythropoiesis in adult mouse spleen.
