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

Abstract

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.

Cell cycle of primitive hematopoietic progenitors decelerated in senescent mice is reactively accelerated after 2-Gy whole-body irradiation

“…28 In addition, single-dose (2-Gy) whole-body irradiation at 6 weeks or 6 months of age induced further upregulation of cyclin D1 and PiK3r1 in the LKS cells in 21-month-old mice. 2 On the basis of these previous observations, it can be hypothesized that, in the steady-state hematopoiesis in old mice, cells in the LKS population proliferate to compensate for their functional impairments within downstream progenitorial daughters. Simultaneously, it may be considered that ineffective hematopoiesis also progresses without any increase in the number of differentiated HPCs with aging.…”

“…10 Moreover, it was reported that beta-catenin, cyclin D1, and PiK3r1 appeared to be downregulated in bone marrow cells of aged mice, 2 suggesting that hematopoiesis in the old group was suppressed in the steady state, specifically that in immature HPCs. In addition, although there was no significant ....................................................................................................................... difference in the cell cycle of CFU-GM or CFU-S9 between the nonirradiated young and old groups, the irradiated young and old groups showed marked differences in the cell-cycle parameters of HPCs.…”

“…The number of peripheral blood cells was determined using a Coulter counter (Sysmex K-4500; Sysmex Co., Kobe, Japan) as described elsewhere. 2 …”

“…2,3 On the other hand, sensitivity to radiation-induced effects (in terms of, e.g., survival, tumorigenesis including leukemia, and suppression of HSCs/HPCs) differs depending on the age at exposure. [4][5][6][7] The sensitivity to radiation-induced effects in old mice (e.g., 21 months of age), is, however, not precisely known yet.…”

Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury

“…Instead, there is a growing amount of preclinical (75, 76) and clinical evidence from the bone marrow transplant field (77, 78), as well as the published finding from radiation accidents such as Tokai-mura (79), that despite the early normalization of circulating cell numbers, measures that solely target recovery of the bone marrow stem cell population numbers fail to restore a fully functional hematopoietic compartment and do not protect against downstream systemic late radiation-induced effects.…”