Long‐term Residual Radiation Effect in the Murine Hematopoietic Stem Cell Compartment^a

Abstract

For the measurement of long-term residual radiation effect in the murine hematopoietic system a test system was developed that quantifies the proliferation ability of progeny of spleen repopulating cells by the proliferation factor (PF). The PF expresses the ratios of 125IUdR incorporation in the recipient spleens at days 3 and 5 following cell transfusion, thus measuring the relative increase in number of proliferating cells. Following 500 rad whole-body gamma irradiation, PF recovered up to 6 months and remained thereafter, on the average, at 80% of control. Recovery of the number of 7-day CFU-S was similar to recovery of PF. Various studies were aimed at elucidating the reasons for reduction in PF. Loss of incorporated 125IUdR activity from spleens between days 3 and 5 after cell transfusion indicates loss of mature labeled cells. When the doubling time of proliferating cells of CFU-S progeny (td) is corrected for cell loss, td for control bone marrow approaches mitotic cycle time in normal bone marrow as was found elsewhere. Following 500 rad, both cell loss and td were initially increased and recovered in parallel with PF and number of CFU-S. Reduction of PF could be brought about by radiation-induced increase in transient CFU-S with the consequence of increased loss of mature cells between days 3 and 5. This possibility was excluded by the observation that 1 year after 500 rad the number of colonies per spleen did not decrease from day 7 to day 12 after cell transfusion, as was expected from a higher proportion of transient CFU-S, but increased more than in the controls. Measurement of these 12-day colonies showed a significantly reduced size. Average progeny from irradiated CFU-S, apparently, grow more slowly. It is concluded that sublethal injury resides in stem cells, increases mitotic cycle time, and causes precocious loss of cells from spleens probably by enhanced differentiation and maturation due to interference with endocellular control of cell proliferation and differentiation. Probably the observed recovery proceeds via replacement of injured stem cells by less injured or normal stem cells.

Short-term injection of antiapoptotic cytokine combinations soon after lethal γ-irradiation promotes survival

“…39 In this study we then focused on long-term follow-up to assess whether the cytokines selected and their combinations could behave as long-term protectors. In fact, if numerous studies conducted in mice have accounted for long-term follow-up, [40][41][42][43] data on the effects in aging irradiated animals of early cytokine administration are lacking. In our study, delayed death mainly observed from day 150 after TBI was likely to occur from hematologic failure (hematopoietic and thrombotic disorders) and nonhematopoietic defects (fibrosis-associated multiorgan failure).…”

“…In contrast, irradiated control animals displayed no response, but a transient profound phase of thrombocytopenia (F.H., M.D., manuscript in preparation) (3) reduced effectiveness of residual stem cells. 41,45 One can wonder whether the level of HSPC depletion could be related to the multiple cytokine composition of the combination (4F and 5F) or short-term treatment and whether in this context high survival rates paradoxically are obtained at the expense of the HSPC compartment. We found that 5F-treated animals exhibited increased BM megakaryocytes.…”

Proliferative compensation of residual radiation damage in the compartment of hematopoietic early progenitor cells of the mouse

“…This pattern of regeneration within the pool of early hematopoietic precursor cells is different from the regeneration of both the quality and the number of CFU-S [5,10,22] and may be an expression of proliferative compensation. This proliferative compensation obviously disguises persisting quantitative and qualitative damage in the compartment of CFU-S and thus expresses an enhanced stimulus for proliferation [23].…”

“…This proliferative compensation obviously disguises persisting quantitative and qualitative damage in the compartment of CFU-S and thus expresses an enhanced stimulus for proliferation [23]. Selfrenewal of other early precursors, such as CFU-C [22], may as well be involved.…”

“…In addition, intracellular lesions are produced in surviving repopulating cells and can be observed even several months after irradiation [1,18]; these lesions can be quantified by a simple assay [11,12,22]. These effects may be partially compensated by increased cycling of the surviving CFU-S [10].…”