Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice

Jianhui Chang, Wei Feng, Yingying Wang, Yi Luo, Antiño R. Allen, Igor Koturbash, Jennifer Turner, Blair Stewart, Jacob Raber, Martin Hauer-Jensen, Daohong Zhou, Lijian Shao

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalRadiation Research
Volume183
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

proton irradiation
stem cells
Whole-Body Irradiation
Hematopoietic Stem Cells
mice
Protons
damage
causes
protons
bone marrow
Radiation
radiation
long term effects
cells
extraterrestrial radiation
health
Bone Marrow
Radiation Effects
Reactive Oxygen Species
Oxidative Stress

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation
  • Medicine(all)

Cite this

Chang, J., Feng, W., Wang, Y., Luo, Y., Allen, A. R., Koturbash, I., ... Shao, L. (2015). Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice. Radiation Research, 183(2), 240-248. https://doi.org/10.1667/RR13887.1

Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice. / Chang, Jianhui; Feng, Wei; Wang, Yingying; Luo, Yi; Allen, Antiño R.; Koturbash, Igor; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian.

In: Radiation Research, Vol. 183, No. 2, 01.02.2015, p. 240-248.

Research output: Contribution to journalArticle

Chang, J, Feng, W, Wang, Y, Luo, Y, Allen, AR, Koturbash, I, Turner, J, Stewart, B, Raber, J, Hauer-Jensen, M, Zhou, D & Shao, L 2015, 'Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice', Radiation Research, vol. 183, no. 2, pp. 240-248. https://doi.org/10.1667/RR13887.1
Chang, Jianhui ; Feng, Wei ; Wang, Yingying ; Luo, Yi ; Allen, Antiño R. ; Koturbash, Igor ; Turner, Jennifer ; Stewart, Blair ; Raber, Jacob ; Hauer-Jensen, Martin ; Zhou, Daohong ; Shao, Lijian. / Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice. In: Radiation Research. 2015 ; Vol. 183, No. 2. pp. 240-248.
@article{61ce4f42d02b476e90964cc5ff2d6ad1,
title = "Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice",
abstract = "Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80{\%} of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.",
author = "Jianhui Chang and Wei Feng and Yingying Wang and Yi Luo and Allen, {Anti{\~n}o R.} and Igor Koturbash and Jennifer Turner and Blair Stewart and Jacob Raber and Martin Hauer-Jensen and Daohong Zhou and Lijian Shao",
year = "2015",
month = "2",
day = "1",
doi = "10.1667/RR13887.1",
language = "English (US)",
volume = "183",
pages = "240--248",
journal = "Radiation Research",
issn = "0033-7587",
publisher = "Radiation Research Society",
number = "2",

}

TY - JOUR

T1 - Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice

AU - Chang, Jianhui

AU - Feng, Wei

AU - Wang, Yingying

AU - Luo, Yi

AU - Allen, Antiño R.

AU - Koturbash, Igor

AU - Turner, Jennifer

AU - Stewart, Blair

AU - Raber, Jacob

AU - Hauer-Jensen, Martin

AU - Zhou, Daohong

AU - Shao, Lijian

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.

AB - Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.

UR - http://www.scopus.com/inward/record.url?scp=84923315652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923315652&partnerID=8YFLogxK

U2 - 10.1667/RR13887.1

DO - 10.1667/RR13887.1

M3 - Article

VL - 183

SP - 240

EP - 248

JO - Radiation Research

JF - Radiation Research

SN - 0033-7587

IS - 2

ER -