Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice

Journal Article · Fri Jul 10 00:00:00 EDT 2015 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0132041· OSTI ID:1903944

Wang, Changshan ^[1]; Oshima, Motohiko ^[2]; Sashida, Goro ^[3]; Tomioka, Takahisa ^[2]; Hasegawa, Nagisa ^[4]; Mochizuki-Kashio, Makiko ^[2]; Nakajima-Takagi, Yaeko ^[2]; Kusunoki, Yoichiro ^[5]; Kyoizumi, Seishi ^[5]; Imai, Kazue ^[5]; Nakachi, Kei ^[5]; Iwama, Atsushi ^[2]

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1. Chiba University (Japan); Inner Mongolia University, Hohhot (China)
2. Chiba University (Japan)
3. Chiba University (Japan); Kumamoto University (Japan)
4. Chiba University (Japan); Chiba University Hospital (Japan)
5. Radiation Effects Research Foundation (RERF), Hiroshima (Japan)

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 IL2rγ^null (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 postirradiation 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.

• Research Organization: Radiation Effects Research Foundation (RERF), Hiroshima (Japan)
• Sponsoring Organization: USDOE; Japanese Ministry of Health, Labor, and Welfare (MHLW); National Institute of Allergy and Infectious Diseases (NIAID)
• Grant/Contract Number: HHSN272200900059C
• OSTI ID: 1903944
• Journal Information: PLoS ONE, Vol. 10, Issue 7; ISSN 1932-6203
• Publisher: Public Library of Science
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
mouse models
B cells
cell diffusion
DNA damage
hematopoietic stem cells
radiation effects
ionizing radiation
regulator genes