title: Total body irradiation selectively induces murine hematopoietic stem cell senescence.
abstract: 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.
authors.affiliation: Department of Pathology & Laboratory Medicine, MUSC, 165 Ashley Ave, Suite 309, Charleston, SC 29425, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Schulte
authors.forename: Amanda C
authors.initials: AC
authors.lastname: LaRue
authors.forename: Makio
authors.initials: M
authors.lastname: Ogawa
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: 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
chemical_list: 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