RERF Report No. 6-15

Paper published in Radiation Research §“Circulating hematopoietic stem and progenitor cells in aging atomic bombsurvivors”
Seishi Kyoizumi, Yoshiko Kubo, Munechika Misumi, Junko Kajimura, Kengo Yoshida,
Tomonori Hayashi, Kazue Imai, Waka Ohishi, Kei Nakachi, Lauren F. Young, Jae-Hung Shieh,
Malcolm A. Moore, Marcel R.M. van den Brink, Yoichiro Kusunoki
Radiat Res 2016 (January); 185(1):69–76(doi: 10.1667/RR14209.1)

Study Findings
Counts of hematopoietic stem and progenitor cells (HSPCs) in the blood of atomic bomb
(A-bomb) survivors decreased with age, but no significant association with radiation dose wasfound.
Explanation
1. Study purpose
Hematopoietic stem cells (HSCs) are known to be highly radiosensitive. Deterioration inhematopoietic function and decrease in peripheral erythrocytes and leukocytes have beenreported as some of the acute effects of radiation observed in A-bomb survivors. However, as aresult of the regenerative capacity of HSCs, hematopoiesis among A-bomb survivors wasreported to have recovered to a considerable extent about 10 weeks after A-bomb radiation
exposure. Nonetheless, gene abnormalities such as mutations persist in the HSCs of A-bomb
survivors even now, 70 years after radiation exposure. To determine whether or not effects ofradiation persist in the HSC function of A-bomb survivors, this study examined the counts ofcirculating hematopoietic stem and progenitor cells per unit volume of blood, as well as their
proportions vis-à-vis all HPSCs in blood, reviewing whether dose-dependent effects of radiation
were observed.
2. Study methods
Peripheral blood was collected from 231 Hiroshima survivors (aged 66–91 years) who hadparticipated in the Adult Health Study (AHS) during the period 2011–2013 and, using a cellsorter, separated CD34-positive/lineage marker-negative (CD34+Lin-) cells thought to contain
HSPCs. The counts of the following types of colony-forming units in this cell population wereevaluated using cell culture: cobblestone area-forming cells*; long-term culture-initiating cells*;
erythroid burst-forming units*; granulocyte and macrophage colony-forming units*; and T-cell1

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and natural killer cell progenitors.* Cobblestone area-forming cells and long-term
culture-initiating cells reflect the self-renewal and the multilineage differentiation functions ofHSCs, respectively. Other colony-forming units reflect lineage-committed hematopoietic
progenitor cells.
Cobblestone area-forming cells: Because these cells form an undifferentiated, cobblestone-like colony inthe absence of hematopoietic factors and under the presence of stromal cells, they are thought tooriginate from self-renewable HSCs.
Long-term culture-initiating cells: Because these cells can produce erythroid burst-forming units andgranulocyte and macrophage colony-forming units over a prolonged period, they are thought tooriginate from HSCs with capacity for multi-lineage differentiation.
Erythroid burst-forming units: Hematopoietic progenitors that can produce erythrocytes
Granulocyte and macrophage colony-forming units: Hematopoietic progenitors that can produce
granulocytes and macrophages
T-cell and natural killer cell progenitors: Hematopoietic progenitors that can produce T lymphocytes orNK lymphocytes

3. Study results(1) Association with age
We found that the counts of CD34+Lin- cells, which are thought to include all HPSCs inblood, significantly decreased with age per unit volume of blood (P = 0.0022). Furthermore,
the counts of respective colony-forming units significantly decreased with age (P = 0.0001–0.0047). As for the proportions of respective colony-forming units in the CD34+Lin- cell
population, only T-cell progenitors decreased with age (P = 0.010), suggesting an
aging-related decline in the stem-cell function (capacity) of T-cell differentiation induction,even among subjects aged around 70 and older.
(2) Association with radiation doseWith regard to the CD34+Lin- cell population and colony-forming units, no significant
effects of radiation exposure were observed in either the absolute cell numbers per unit
volume of blood or in their proportions vis-à-vis all HPSCs in blood.
Study SignificanceOur findings showed that aging in HSC function continued, even among subjects aged
around 70 and older. Specifically with regard to T cells, it is believed that decline in thymic
function induces a decrease in mature peripheral naïve T cells.* This study, however, revealed
that decline in the stem-cell function of T-cell differentiation induction due to stem cell aging
was one reason for the aforementioned decrease. This study also suggests that the numbers and2

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function of HSPCs overall in living A-bomb survivors have recovered to normal levels even as
the survivors aged over the decades since A-bomb radiation exposure (compared to the levels in
unexposed individuals of the same ages).
Mature naïve T cells: Different from T-cell progenitors shown in the fifth line of (1) “Association withage” under the section titled “3. Study results,” these cells are mature lymphocytes that arise bydifferentiation from T-cell progenitors in the thymic environment and differentiate into memory T
cells in response to antigen stimulation in the periphery. This study suggested the possibility thataging of HSCs decreased production of T-cell progenitors, resulting in a decrease in thymic
production of mature naïve T cells.

The Radiation Effects Research Foundation has studied A-bomb survivors and their offspring in
Hiroshima and Nagasaki for more than 60 years. RERF’s research achievements are considered theprincipal scientific basis for radiation risk assessment by the United Nations Scientific Committee on theEffects of Atomic Radiation (UNSCEAR) and for recommendations regarding radiation protection
standards by the International Commission on Radiological Protection (ICRP). RERF expresses its
profound gratitude to the A-bomb survivors and survivors’ offspring for their cooperation in our studies.

§Radiation Research, which is an official monthly journal of the Radiation Research Society, publishes

original, peer-reviewed papers and review articles on radiation effects and related issues in the fields ofphysics, chemistry, biology, and medicine. (Impact factor in 2014: 2.911)3