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

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 ) and their littermate controls (Wls ). 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 mice but not in those of the Col-Cre;Wls mice. TBI-exposed Wls mice exhibited greater impairments in hematopoietic development, colony formation, and long-term repopulation than TBI-exposed Col-Cre;Wls mice. Transplantation with BM HSCs or whole BM cells derived from the mutant, but not Wls mice, protected against HSC senescence and hematopoietic skewing toward myeloid cells and enhanced survival in recipients of lethal TBI (10 Gy). Unlike the Wls mice, the Col-Cre;Wls 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.