Ionizing radiation–induced expression of INK4a/ARF in murine bone marrow–derived stromal cell populations interferes with bone marrow homeostasis

• Published in: Blood 2012-01, Vol.119 (3), p.717-726
• Main Authors: Carbonneau, Cynthia L., Despars, Geneviève, Rojas-Sutterlin, Shanti, Fortin, Audrey, Le, Oanh, Hoang, Trang, Beauséjour, Christian M.
• Format: Article
• Language: English
• Subjects: ADP-Ribosylation Factor 1 - physiology; Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Marrow - radiation effects; Cell Differentiation; Cell Proliferation; Cellular Senescence - radiation effects; Cyclin-Dependent Kinase Inhibitor p16 - physiology; Female; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - radiation effects; Homeostasis - radiation effects; Lymphopoiesis - radiation effects; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Radiation, Ionizing; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; Stromal Cells - metabolism; Stromal Cells - pathology; Stromal Cells - radiation effects
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-06-361626

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 p16INK4a/p19ARF 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.