Abstract
We quantitated age-related accumulation of senescent cells in irradiated Fanconi anemia (FA) (Fanca(-/-) mouse cell lines in vitro, and monitored the effect of continuous administration (via drinking water) of the water-soluble radiation mitigator, MMS350, on tissues in vivo over one year after 7.5 Gy total-body irradiation (TBI). Irradiated Fanca(-/-) mouse bone marrow stromal cell lines showed increased numbers of beta-galactosidase- and p21-positive senescent cells compared to Fanca(+/+) cell lines, which was reduced by MMS350. One week after 7.5 Gy TBI, Fanca(-/-) mice showed increased numbers of senescent cells in spleen compared to Fanca(+/+) controls, decreased bone marrow cellularity, failure of explanted bone marrow to proliferate in vitro to form a hematopoietic microenvironment and no detectable single stromal cell cloning capacity. There was no detectable amelioration by MMS350 administration at one week. In contrast, one year post-TBI, Fanca(-/-) mice demonstrated fewer senescent cells in brain and spleen compared to Fanca(+/+) controls. While Fanca(-/-) mouse bone marrow stromal cells explanted one year post-TBI still failed to proliferate in vitro, continuous oral administration of 400 µ M, MMS350 in drinking water restored explanted stromal cell proliferation. The data indicate that continuous administration of MMS350 modulated several properties of TBI-accelerated aging in Fanca(-/-) mice as well as control mice, and support further study of MMS350 as a modulator of radiation late effects.