title: Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice.
abstract: Precise understanding of radiation effects is critical to develop new modalities for the prevention and treatment of radiation-induced damage. We previously reported that non-lethal doses of X-ray irradiation induce DNA damage in human hematopoietic stem and progenitor cells (HSPCs) reconstituted in NOD/Shi-scid IL2rγnull (NOG) immunodeficient mice and severely compromise their repopulating capacity. In this study, we analyzed in detail the functional changes in human HSPCs in NOG mice following non-lethal radiation. We transplanted cord blood CD34+ HSPCs into NOG mice. At 12 weeks post-transplantation, the recipients were irradiated with 0, 0.5, or 1.0 Gy. At 2 weeks post-irradiation, human CD34+ HSPCs recovered from the primary recipient mice were transplanted into secondary recipients. CD34+ HSPCs from irradiated mice showed severely impaired reconstitution capacity in the secondary recipient mice. Of interest, non-lethal radiation compromised contribution of HSPCs to the peripheral blood cells, particularly to CD19+ B lymphocytes, which resulted in myeloid-biased repopulation. Co-culture of limiting numbers of CD34+ HSPCs with stromal cells revealed that the frequency of B cell-producing CD34+ HSPCs at 2 weeks post-irradiation was reduced more than 10-fold. Furthermore, the key B-cell regulator genes such as IL-7R and EBF1 were downregulated in HSPCs upon 0.5 Gy irradiation. Given that compromised repopulating capacity and myeloid-biased differentiation are representative phenotypes of aged HSCs, our findings indicate that non-lethal ionizing radiation is one of the critical external stresses that promote aging of human HSPCs in the bone marrow niche.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; College of Life Sciences, Inner Mongolia University, Hohhot 010021, China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; International Research Center for Medical Sciences, Kumamoto University, Kumamoto City 860-0811, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Tomioka
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Department of Hematology, Chiba University Hospital, Chiba 260-8670, Japan.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Hasegawa
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.affiliation: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusunoki
authors.affiliation: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Kyoizumi
authors.affiliation: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nakachi
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006410:Hematopoiesis / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000528:radiation effects; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D011839:Radiation, Ionizing