Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

We have previously demonstrated that mitigation of lethal irradiation by growth hormone is associated with an increase of insulin-like growth factor 1 (IGF-1) level in blood, suggesting that IGF-1 may be able to mitigate against lethal irradiation. In this study, we tested this possibility directly. BALB/c mice first received 7.5 Gy of total body radiation. Within one hour after irradiation, the mice were then treated with IGF-1 at a dose of 100 mg/dose, i.v., once a day for 5 consecutive days. In the saline control group, 2 out of 20 mice (10%) survived more than 100 days after irradiation. By contrast, 8 out of 20 mice (40%) in the IGF-1-treated group survived more than 100 days after irradiation (P<0.01). A single dose of IGF-1 (500 mg) given within one hour after irradiation was as effective as the 5-day dose. IGF-1 remained effective when the treatment was delayed for at least up to 6 hours post irradiation. Moreover, the radio-protective effect of IGF-1 was still evident when higher dose of radiation (8.5 Gy, LD100/30) was used. Similar effects were also observed in a second strain of mice (C57BL/6). Because hematopoietic system is most sensitive to total body irradiation, we next sought to determine the effects of IGF-1 on hematopoietic recovery. Compared with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red cells in blood in irradiated (7.5 Gy) BALB/c mice when measured at day +14 post irradiation. Numbers of total bone marrow cells as well as hematopoietic stem cells and progenitors per femur were significantly increased in IGF-1-treated mice compared with the control group. Using flow cytometric analysis and a novel single cell assay, we demonstrated that IGF-1 protected both hematopoietic stem cells and progenitors from radiation-induced apoptosis and cell death. Using an in vitro culture system, we also demonstrated that IGF-1 was able to facilitate the proliferation and differentiation of non-irradiated and irradiated hematopoietic progenitors but not stem cells. These data indicate that IGF-1 mitigates against lethal irradiation through protecting hematopoietic stem/progenitor cells from radiation-induced apoptosis and also through enhancing proliferation and differentiation of surviving hematopoietic progenitor cells.