Osteoblastic Wls Ablation Protects Mice from Total Body Irradiation-Induced Impairments in Hematopoiesis and Bone Marrow Microenvironment

Abstract

Ionizing irradiation (IR) causes bone marrow (BM) injury, with senescence and impaired self-renewal of hematopoietic stem cells (HSCs), and inhibiting Wnt signaling could enhance hematopoietic regeneration and survival against IR stress. However, the underlying mechanisms by which a Wnt signaling blockade modulates IR-mediated damage of BM HSCs and mesenchymal stem cells (MSCs) are not yet completely understood. We investigated the effects of osteoblastic Wntless ( Wls ) depletion on total body irradiation (TBI, 5 Gy)-induced impairments in hematopoietic development, MSC function, and the BM microenvironment using conditional Wls knockout mutant mice ( Col-Cre ; Wls fl/fl ) and their littermate controls ( Wls fl/fl ). Osteoblastic Wls ablation itself did not dysregulate BM frequency or hematopoietic development at a young age. Exposure to TBI at 4 weeks of age induced severe oxidative stress and senescence in the BM HSCs of Wls fl/fl mice but not in those of the Col-Cre ; Wls fl/fl mice. TBI-exposed Wls fl/fl mice exhibited greater impairments in hematopoietic development, colony formation, and long-term repopulation than TBI-exposed Col-Cre ; Wls fl/fl mice. Transplantation with BM HSCs or whole BM cells derived from the mutant, but not Wls fl/fl mice, protected against HSC senescence and hematopoietic skewing toward myeloid cells and enhanced survival in recipients of lethal TBI (10 Gy). Unlike the Wls fl/fl mice, the Col-Cre ; Wls fl/fl mice also showed radioprotection against TBI-mediated MSC senescence, bone mass loss, and delayed body growth. Our results indicate that osteoblastic Wls ablation renders BM-conserved stem cells resistant to TBI-mediated oxidative injuries. Overall, our findings show that inhibiting osteoblastic Wnt signaling promotes hematopoietic radioprotection and regeneration.