title: Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors.
abstract: Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34+Lin-) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure.
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan. Electronic address: kajimura@rerf.or.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Kajimura
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Kyoizumi
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kubo
authors.affiliation: Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Munechika
authors.initials: M
authors.lastname: Misumi
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Waka
authors.initials: W
authors.lastname: Ohishi
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nakachi
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Nan-Ping
authors.initials: NP
authors.lastname: Weng
authors.affiliation: Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.affiliation: Department of Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jae-Hung
authors.initials: JH
authors.lastname: Shieh
authors.affiliation: Department of Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Moore
authors.affiliation: Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Departments of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Japan. Electronic address: ykusunok@rerf.or.jp.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusunoki
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D006657:Histones
keywords: Atomic-bomb; DNA damage; Hematopoietic stem and progenitor cells; Self-renewability; Telomere length; γH2AX