title: Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice.
abstract: Exposure to ionizing radiation (IR) increases the production of reactive oxygen species (ROS) not only by the radiolysis of water but also through IR-induced perturbation of the cellular metabolism and disturbance of the balance of reduction/oxidation reactions. Our recent studies showed that the increased production of intracellular ROS induced by IR contributes to IR-induced late effects, particularly in the hematopoietic system, because inhibition of ROS production with an antioxidant after IR exposure can mitigate IR-induced long-term bone marrow (BM) injury. Metformin is a widely used drug for the treatment of type 2 diabetes. Metformin also has the ability to regulate cellular metabolism and ROS production by activating AMP-activated protein kinase. Therefore, we examined whether metformin can ameliorate IR-induced long-term BM injury in a total-body irradiation (TBI) mouse model. Our results showed that the administration of metformin significantly attenuated TBI-induced increases in ROS production and DNA damage and upregulation of NADPH oxidase 4 expression in BM hematopoietic stem cells (HSCs). These changes were associated with a significant increase in BM HSC frequency, a considerable improvement in in vitro and in vivo HSC function, and complete inhibition of upregulation of p16(Ink4a) in HSCs after TBI. These findings demonstrate that metformin can attenuate TBI-induced long-term BM injury at least in part by inhibiting the induction of chronic oxidative stress in HSCs and HSC senescence. Therefore, metformin has the potential to be used as a novel radioprotectant to ameliorate TBI-induced long-term BM injury.
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors.forename: Guoshun
authors.initials: G
authors.lastname: Xu
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Wu
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China. Electronic address: ldguan@163.com.
authors.forename: Deguan
authors.initials: D
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China; Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China; Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China; Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: DZhou@uams.edu.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China; Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China. Electronic address: ai_min_meng@126.com.
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014916:Whole-Body Irradiation
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D008687:Metformin
keywords: Free radicals; Hematopoietic stem cells; Ionizing radiation; Metformin; Oxidative stress; Radioprotection