Total body irradiation selectively induces murine hematopoietic stem cell senescence

Exposure to ionizing radiation (IR) and certain chemotherapeutic agents not only causes acute bone marrow (BM) suppression but also leads to long-term residual hematopoietic injury. This latter effect has been attributed to damage to hematopoietic stem cell (HSC) self-renewal. Using a mouse model, we investigated whether IR induces senescence in HSCs, as induction of HSC senescence can lead to the defect in HSC self-renewal. It was found that exposure of C57BL/6 mice to a sublethal dose (6.5 Gy) of total body irradiation (TBI) resulted in a sustained quantitative and qualitative reduction of LKS ⁺ HSCs. In addition, LKS⁺ HSCs from irradiated mice exhibited an increased expression of the 2 commonly used biomarkers of cellular senescence, p16^Ink4a and SA-β-gal. In contrast, no such changes were observed in irradiated LKS^- hematopoietic progenitor cells. These results provide the first direct evidence demonstrating that IR exposure can selectively induce HSC senescence. Of interest, the induction of HSC senescence was associated with a prolonged elevation of p21^Cip1/Waf1, p19^Arf, and p16^Ink4a mRNA expression, while the expression of p27^Kip1 and p18^Ink4c mRNA was not increased following TBI. This suggests that p21^Cip1/Waf1, p19^Arf, and p16^Ink4a may play an important role in IR-induced senescence in HSCs.