title: Disruption of Notch signaling aggravates irradiation-induced bone marrow injury, which is ameliorated by a soluble Dll1 ligand through Csf2rb2 upregulation.
abstract: Physical and chemical insult-induced bone marrow (BM) damage often leads to lethality resulting from the depletion of hematopoietic stem and progenitor cells (HSPCs) and/or a deteriorated BM stroma. Notch signaling plays an important role in hematopoiesis, but whether it is involved in BM damage remains unclear. In this study, we found that conditional disruption of RBP-J, the transcription factor of canonical Notch signaling, increased irradiation sensitivity in mice. Activation of Notch signaling with the endothelial cell (EC)-targeted soluble Dll1 Notch ligand mD1R promoted BM recovery after irradiation. mD1R treatment resulted in a significant increase in myeloid progenitors and monocytes in the BM, spleen and peripheral blood after irradiation. mD1R also enhanced hematopoiesis in mice treated with cyclophosphamide, a chemotherapeutic drug that induces BM suppression. Mechanistically, mD1R increased the proliferation and reduced the apoptosis of myeloid cells in the BM after irradiation. The β chain cytokine receptor Csf2rb2 was identified as a downstream molecule of Notch signaling in hematopoietic cells. mD1R improved hematopoietic recovery through up-regulation of the hematopoietic expression of Csf2rb2. Our findings reveal the role of Notch signaling in irradiation- and drug-induced BM suppression and establish a new potential therapy of BM- and myelo-suppression induced by radiotherapy and chemotherapy.
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Gao
authors.affiliation: Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jun-Chang
authors.initials: JC
authors.lastname: Li
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Sun
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Si-Yong
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Yi-Zhe
authors.initials: YZ
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Ying-Min
authors.initials: YM
authors.lastname: Liang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qin
authors.affiliation: Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D000818:Animals; D001773:Blood Cells; D001853:Bone Marrow / Q000502:physiology* / Q000528:radiation effects; D002135:Calcium-Binding Proteins; D020022:Genetic Predisposition to Disease; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000502:physiology; D011833:Radiation Injuries, Experimental / Q000503:physiopathology*; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D036341:Intercellular Signaling Peptides and Proteins; C497571:Rbpj protein, mouse; D016185:Receptors, Interleukin-3; C072185:Csf2rb2 protein, mouse