Late Effects of X-irradiation on Haemopoietic Stem Cells in CBA/H Mice

Lorimore, Sally A.; Wright, E. A.

doi:10.1080/09553009014552481

Cited by 13 publications

(9 citation statements)

References 15 publications

(10 reference statements)

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“…The frequency of MPP is suboptimal in that condition even if the cells cycle more rapidly than in the normal state. This indication is consistent with the reported late effects of x-irradiation on CFU-S (Lorimore and Wright, 1990). On the basis of cell kinetics estimated by the simulation, the number of cell divisions of each cell type was calculated.…”

Section: Discussionsupporting

confidence: 73%

“…In this regard, early studies on haematopoietic effects of radiation present intriguing data. The frequency of CFU-S is depressed while the level of cycling is increased over the lifespan of x-irradiated mice (Tejero et al, 1988;Lorimore and Wright, 1990). If HSCs also cycle at enhanced rates for a prolonged period of time, the replicative stress will result in premature ageing.…”

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confidence: 99%

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Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia

Ban

Kai

2009

Br J Cancer

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BACKGROUND: The essential aetiology of radiation-induced acute myeloid leukaemia (AML) in mice is the downregulation of the transcription factor PU.1. The causative mutation of the PU.1-endocing Sfpi1 gene consists mostly of C:G to T:A transitions at a CpG site and is likely to be of spontaneous origin. To work out a mechanism underlying the association between radiation exposure and the AML induction, we have hypothesised that replicative stress after irradiation accelerates the ageing of haematopoietic stem cells (HSCs), and the ageing-related decline in DNA repair could affect the spontaneous mutation rates. METHODS: Mathematical model analysis was conducted to examine whether and to what extent the cell kinetics of HSCs can be modified after irradiation. The haematopoietic differentiation process is expressed as a mathematical model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data. RESULTS: The analysis revealed that HSCs cycle vigourously for more than a few months after irradiation. The estimated number of cell divisions per surviving HSC in 3 Gy-exposed mice reached as high as ten times that of the unexposed. INTERPRETATION: The mitotic load after 3 Gy irradiation seems to be heavy enough to accelerate the ageing of HSCs and the hypothesis reasonably explains the leukaemogenic process.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia

Ban

Kai

2009

Br J Cancer

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“…Senescence is associated with xenobiotic responses throughout the life span that include age‐related accumulation of xenobiotic metabolic products, epigenetic senescent damage, and changes owing to genomic instability. Several groups of investigators have assessed radiation‐associated alterations of the frequency of recovery in hematopoietic stem/progenitor cells (HSCs/HPCs) and/or gene expression in these subpopulations . The results of their investigations suggest that (1) the recovery of the number of primitive and slightly differentiated stem/progenitor cells after radiation exposure depends on the hierarchy in relation to generation‐age structure during blood cell differentiation, and (2) ionizing radiation induces the expression of particular genes, the products of which are involved in cellular processes, such as cell cycle progression, growth regulation, and apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Radiation‐induced, cell cycle–related gene expression in aging hematopoietic stem cells: enigma of their recovery

Hirabayashi

2014

Annals of the New York Academy of Sciences

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This paper reviews quantitative and qualitative studies conducted to identify changes in the characteristics of hematopoietic stem/progenitor cells (HSCs/HPCs) with or without radiation exposure. The numerical recovery of HSCs/HPCs after radiation exposure is lower than for other types of cells, an effect that may depend on hierarchical ordering of generation age during blood cell differentiation, from primitive HSCs to various differentiated HPCs. Studies are in progress to evaluate gene expression in bone marrow cells and cells in the lineage-negative, c-Kit(+), stem cell antigen(+) (LKS) fraction from 21-month-old mice, with or without radiation exposure. Preliminary data suggest that cell cycle-related genes, that is, cyclin D1 (Ccnd1), phosphatidylinositol 3 kinase regulatory subunit polypeptide 1 (PiK3r1), and Fyn, are upregulated solely in the LKS fraction from 21-month-old mice irradiated at 6 weeks of age, compared with the LKS fraction from age-matched nonirradiated control mice. Additional studies may provide evidence that the aging phenotype is exaggerated following exposure to ionizing radiation, specifically in the LKS fraction.

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“…cells in the lineage‐negative, c‐kit‐positive, and stem‐cell‐antigen‐1‐positive (LKS) fraction, the number of which prominently decreases and does not seem to recover, at least until 19.5 months after irradiation. Interestingly, the recovery of the number of hematopoietic cells after radiation exposure was much delayed, as long as the differentiation of these cells from the most undifferentiated fraction to a differentiated fraction (Cronkite et al ., ; Lorimore and Wright, ; Wang et al ., ; Hirabayashi, ). Furthermore, even although the cells in the LKS fraction may recover in number, primitive blood cells, particularly those in the LKS fraction, remain undifferentiated or undergo accelerated aging.…”

Section: Introductionmentioning

confidence: 99%

Experimentally induced, synergistic late effects of a single dose of radiation and aging: significance in LKS fraction as compared with mature blood cells

Hirabayashi

Tsuboi

Nakachi

et al. 2014

J of Applied Toxicology

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The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation at 6 weeks of age, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell (HSC/HPC) compartment [cells in the lineage-negative, c-kit-positive and stem-cell-antigen-1-positive (LKS) fraction], the numerical differences between mice with and without irradiation remained more than a year, but conclusively the cells showed numerical recovery. When mice were exposed to radiation at 6 months of age, acute damages of mature blood cells were rather milder probably because of their maturation with age; but again, cells in the LKS fraction were specifically damaged, and their numerical recovery was significantly delayed probably as a result of LKS-specific cellular damages. Interestingly, in contrast to the recovery of the number of cells in the LKS fraction, their quality was not recovered, which was quantitatively assessed on the basis of oxidative-stress-related fluorescence intensity. To investigate why the recovery in the number of cells in the LKS fraction was delayed, expression levels of genes related to cellular proliferation and apoptosis of cells in the bone marrow and LKS fraction were analyzed by real-time polymerase chain reaction (RT-PCR). In the case of 21-month-old mice after radiation exposure, Ccnd1, PiK3r1 and Fyn were overexpressed solely in cells in the LKS fraction. Because Ccnd1and PiK3r1 upregulated by aging were further upregulated by radiation, single-dose radiation seemed to induce the acceleration of aging, which is related to the essential biological responses during aging based on a lifetime-dependent relationship between a living creature and xenobiotic materials.

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Late Effects of X-irradiation on Haemopoietic Stem Cells in CBA/H Mice

Cited by 13 publications

References 15 publications

Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia

Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia

Radiation‐induced, cell cycle–related gene expression in aging hematopoietic stem cells: enigma of their recovery

Experimentally induced, synergistic late effects of a single dose of radiation and aging: significance in LKS fraction as compared with mature blood cells

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