title: Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Laboratory Animal Science, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China ; Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Xing
authors.affiliation: The First Central Clinical College of Tianjin Medical University, Tianjin First Central Hospital, Tianjin, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Deguan
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Laboratory Animal Science, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China ; Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China ; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
keywords: G-CSF; HSC; Ionizing radiation