title: Ionizing radiation-induced expression of INK4a/ARF in murine bone marrow-derived stromal cell populations interferes with bone marrow homeostasis.
abstract: Alterations of the BM microenvironment have been shown to occur after chemoradiotherapy, during aging, and after genetic manipulations of telomere length. Nevertheless, whether BM stromal cells adopt senescent features in response to these events is unknown. In the present study, we provide evidence that exposure to ionizing radiation (IR) leads murine stromal BM cells to express senescence markers, namely senescence-associated β-galactosidase and increased p16(INK4a)/p19(ARF) expression. Long (8 weeks) after exposure of mice to IR, we observed a reduction in the number of stromal cells derived from BM aspirates, an effect that we found to be absent in irradiated Ink4a/arf-knockout mice and to be mostly independent of the CFU potential of the stroma. Such a reduction in the number of BM stromal cells was specific, because stromal cells isolated from collagenase-treated bones were not reduced after IR. Surprisingly, we found that exposure to IR leads to a cellular nonautonomous and Ink4a/arf-dependent effect on lymphopoiesis. Overall, our results reveal the distinct sensitivity of BM stromal cell populations to IR and suggest that long-term residual damage to the BM microenvironment can influence hematopoiesis in an Ink4a/arf-dependent manner.
authors.affiliation: Centre de recherche du Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, QC, Canada.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Carbonneau
authors.forename: Geneviève
authors.initials: G
authors.lastname: Despars
authors.forename: Shanti
authors.initials: S
authors.lastname: Rojas-Sutterlin
authors.forename: Audrey
authors.initials: A
authors.lastname: Fortin
authors.forename: Oanh
authors.initials: O
authors.lastname: Le
authors.forename: Trang
authors.initials: T
authors.lastname: Hoang
authors.forename: Christian M
authors.initials: CM
authors.lastname: Beauséjour
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000528:radiation effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006706:Homeostasis / Q000528:radiation effects*; D038041:Lymphopoiesis / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D020823:ADP-Ribosylation Factor 1