The Notch signaling pathway regulates intestinal epithelial cell homeostasis,including stem cell maintenance, progenitor cell proliferation and differentiation.Recently, we designed and produced an endothelium-targeted soluble Notch ligand,the DSL domain of Delta-like 1 fused with a RGD motif (D 1R), then reported its radioresistant role in hematopoietic system.In of this study, DR was to determine the effects on ionizing radiation (IR)-induced intestinal stem cell (ISC) deletion, crypt and overall survival following lethal TBI.C57BL/6 mice were exposed to TBI (8-14 Gy) and euthanized at 6 and 84h post-IR to assess ISC deletion and crypt survival respectively.In D1R treatment group, we observed a obvious increase in ISC/crypt survival, and increased expression of, Lgr5, Bmi1, and Notch1 (in small intestine)post-TBI in D1R treated mice compared to controls.Cultured with mice intestinal decellularized scaffold ex vivo, we also observed improving increased both ISCs expansion engraftment ex vivo compared to controls.Given the radioresistant role activity of D1R, our data support a potential role for D1R as an agent that can be administered to patients receiving radiation therapy to protect against radiation-induces mucositis.