Physical and chemical causes-induced bone marrow (BM) damage often leads to lethality due to neutropenia, thrombocytopenia and anemia, as well as infection resulted from the depletion of hematopoietic stem and progenitor cells (HSPCs) and/or deteriorated BM stroma.The Notch signaling pathway plays a pivotal role in regulating multiple aspects of?the?hematopoiesis during embryonic and postnatal development by mediating HSPCs-stroma interaction, but the role of this pathway in BM recovery after irradiation has been elusive.In this study, we show that conditional disruption of RBP-J, the transcription factor of canonical Notch signaling, increased irradiation sensitivity in mice.We further show that mD1R, a fusion peptide composed of the DSL domain of mouse Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs), dosage-dependently promoted BM recovery after irradiation, mD1R treatment resulted in a significant increase in myeloid progenitors and Ly6G+/CD11b+ double positive monocytes in BM, spleen and peripheral blood after total body irradiation (TBI), suggesting that mD1R enhanced myeloid reconstitution after irradiation and might have a specific effect on short-term HSCs with myeloid repopulating potential.Mechanistically, mD1R could increase the proliferation and reduce the apoptosis of myeloid cells in BM after irradiation.Our findings establish a new potential therapy to irradiation-induced BMand myelo-suppression, which could be a consequence of increased myeloid proliferation and survival.