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-beta-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.
Wang
Yong
Y
Department of Pathology & Laboratory Medicine, MUSC, 165 Ashley Ave, Suite 309, Charleston, SC 29425, USA.
Schulte
Bradley A
BA
LaRue
Amanda C
AC
Ogawa
Makio
M
Zhou
Daohong
D
D000818:Animals; D016922:Cellular Senescence / Q000528:radiation effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000528:radiation effects; D014916:Whole-Body Irradiation
C493957:Cdkn1a protein, mouse; C493975:Cdkn2d protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger