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Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation

BACKGROUND: Exposure to a moderate to high dose of ionizing radiation (IR) not only causes acute radiation syndrome but also induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Granulocyte colon...

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Autores principales: Li, Chengcheng, Lu, Lu, Zhang, Junling, Huang, Song, Xing, Yonghua, Zhao, Mingfeng, Zhou, Daohong, Li, Deguan, Meng, Aimin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659162/
https://www.ncbi.nlm.nih.gov/pubmed/26609358
http://dx.doi.org/10.1186/s13578-015-0057-3
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author Li, Chengcheng
Lu, Lu
Zhang, Junling
Huang, Song
Xing, Yonghua
Zhao, Mingfeng
Zhou, Daohong
Li, Deguan
Meng, Aimin
author_facet Li, Chengcheng
Lu, Lu
Zhang, Junling
Huang, Song
Xing, Yonghua
Zhao, Mingfeng
Zhou, Daohong
Li, Deguan
Meng, Aimin
author_sort Li, Chengcheng
collection PubMed
description BACKGROUND: Exposure to a moderate to high dose of ionizing radiation (IR) not only causes acute radiation syndrome but also induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Granulocyte colony-stimulating factor (G-CSF) is the only treatment recommended to be given to radiation victims soon after IR. However, clinical studies have shown that G-CSF used to treat the leukopenia induced by radiotherapy or chemotherapy in patients can cause sustained low white blood cell counts in peripheral blood. It has been suggested that this adverse effect is caused by HSC and hematopoietic progenitor cell (HPC) proliferation and differentiation stimulated by G-CSF, which impairs HSC self-renewal and may exhaust the BM capacity to exacerbate IR-induced LT-BM injury. METHODS: C57BL/6 mice were exposed to 4 Gy γ-rays of total body irradiation (TBI) at a dose-rate of 1.08 Gy per minute, and the mice were treated with G-CSF (1 μg/each by ip) or vehicle at 2 and 6 h after TBI on the first day and then twice every day for 6 days. All mice were killed one month after TBI for analysis of peripheral blood cell counts, bone marrow cellularity and long-term HSC (CD34-lineage-sca1+c-kit+) frequency. The colony-forming unit-granulocyte and macrophage (CFU-GM) ability of HPC was measured by colony-forming cell (CFC) assay, and the HSC self-renewal capacity was analyzed by BM transplantation. The levels of ROS production, the expression of phospho-p38 mitogen-activated protein kinase (p-p38) and p16(INK4a) (p16) mRNA in HSCs were measured by flow cytometry and RT-PCR, respectively. RESULTS: The results of our studies show that G-CSF administration mitigated TBI-induced decreases in WBC and the suppression of HPC function (CFU-GM) (p < 0.05), whereas G-CSF exacerbated the suppression of long-term HSC engraftment after transplantation one month after TBI (p < 0.05); The increase in HSC damage was associated with increased ROS production, activation of p38 mitogen-activated protein kinase (p38), induction of senescence in HSCs. CONCLUSION: Our findings suggest that although G-CSF administration can reduce ARS, it can also exacerbate TBI-induced LT-BM injury in part by promoting HSC senescence via the ROS-p38-p16 pathway.
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spelling pubmed-46591622015-11-26 Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation Li, Chengcheng Lu, Lu Zhang, Junling Huang, Song Xing, Yonghua Zhao, Mingfeng Zhou, Daohong Li, Deguan Meng, Aimin Cell Biosci Research BACKGROUND: Exposure to a moderate to high dose of ionizing radiation (IR) not only causes acute radiation syndrome but also induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Granulocyte colony-stimulating factor (G-CSF) is the only treatment recommended to be given to radiation victims soon after IR. However, clinical studies have shown that G-CSF used to treat the leukopenia induced by radiotherapy or chemotherapy in patients can cause sustained low white blood cell counts in peripheral blood. It has been suggested that this adverse effect is caused by HSC and hematopoietic progenitor cell (HPC) proliferation and differentiation stimulated by G-CSF, which impairs HSC self-renewal and may exhaust the BM capacity to exacerbate IR-induced LT-BM injury. METHODS: C57BL/6 mice were exposed to 4 Gy γ-rays of total body irradiation (TBI) at a dose-rate of 1.08 Gy per minute, and the mice were treated with G-CSF (1 μg/each by ip) or vehicle at 2 and 6 h after TBI on the first day and then twice every day for 6 days. All mice were killed one month after TBI for analysis of peripheral blood cell counts, bone marrow cellularity and long-term HSC (CD34-lineage-sca1+c-kit+) frequency. The colony-forming unit-granulocyte and macrophage (CFU-GM) ability of HPC was measured by colony-forming cell (CFC) assay, and the HSC self-renewal capacity was analyzed by BM transplantation. The levels of ROS production, the expression of phospho-p38 mitogen-activated protein kinase (p-p38) and p16(INK4a) (p16) mRNA in HSCs were measured by flow cytometry and RT-PCR, respectively. RESULTS: The results of our studies show that G-CSF administration mitigated TBI-induced decreases in WBC and the suppression of HPC function (CFU-GM) (p < 0.05), whereas G-CSF exacerbated the suppression of long-term HSC engraftment after transplantation one month after TBI (p < 0.05); The increase in HSC damage was associated with increased ROS production, activation of p38 mitogen-activated protein kinase (p38), induction of senescence in HSCs. CONCLUSION: Our findings suggest that although G-CSF administration can reduce ARS, it can also exacerbate TBI-induced LT-BM injury in part by promoting HSC senescence via the ROS-p38-p16 pathway. BioMed Central 2015-11-25 /pmc/articles/PMC4659162/ /pubmed/26609358 http://dx.doi.org/10.1186/s13578-015-0057-3 Text en © Li et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Li, Chengcheng
Lu, Lu
Zhang, Junling
Huang, Song
Xing, Yonghua
Zhao, Mingfeng
Zhou, Daohong
Li, Deguan
Meng, Aimin
Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
title Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
title_full Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
title_fullStr Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
title_full_unstemmed Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
title_short Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
title_sort granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659162/
https://www.ncbi.nlm.nih.gov/pubmed/26609358
http://dx.doi.org/10.1186/s13578-015-0057-3
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