Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice.
Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice.
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DOI：
10.1371/journal.pone.0132041
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Iwama A
中科院分区：
文献类型：
--
作者：
Wang C;Oshima M;Sashida G;Tomioka T;Hasegawa N;Mochizuki-Kashio M;Nakajima-Takagi Y;Kusunoki Y;Kyoizumi S;Imai K;Nakachi K;Iwama A
准确了解辐射效应对于制定预防和治疗辐射引起的损害的新模式至关重要。我们先前报道了非致死剂量的X射线照射诱导NOD/Shi-scid IL 2 r γnull（NOG）免疫缺陷小鼠中重建的人造血干细胞和祖细胞（HSPCs）的DNA损伤，并严重损害其再生能力。在这项研究中，我们详细分析了非致死性辐射后NOG小鼠中人HSPCs的功能变化。我们将脐带血CD 34 + HSPCs移植到NOG小鼠中。在移植后12周，接受者接受0，0.5，或1.0戈伊的照射。在照射后2周，将从初级受体小鼠回收的人CD 34 + HSPC移植到次级受体中。来自辐射小鼠的CD 34 + HSPC在次级受体小鼠中显示出严重受损的重建能力。值得关注的是，非致死性辐射损害了HSPC对外周血细胞的贡献，特别是对CD 19 + B淋巴细胞的贡献，这导致了骨髓偏向性的再增殖。有限数量的CD 34 + HSPC与基质细胞的共培养显示，在照射后2周，产生B细胞的CD 34 + HSPC的频率降低超过10倍。此外，在0.5戈伊照射后，HSPCs中的关键B细胞调节基因如IL-7 R和EBF 1下调。鉴于受损的再增殖能力和骨髓偏向性分化是老化HSC的代表性表型，我们的研究结果表明，非致死性电离辐射是促进骨髓生态位中人类HSPC老化的关键外部应激之一。
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.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
23.9
作者：
Dykstra, Brad;Kent, David;Eaves, Connie
通讯作者：
Eaves, Connie
影响因子：
64.8
作者：
FULOP, GM;PHILLIPS, RA
通讯作者：
PHILLIPS, RA
影响因子：
7.8
作者：
Kuranda, Klaudia;Vargaftig, Jacques;Goodhardt, Michele
通讯作者：
Goodhardt, Michele
影响因子：
8
作者：
Attema, J. L.;Pronk, C. J. H.;Bryder, D.
通讯作者：
Bryder, D.