Disruption of Notch signaling aggravates irradiation-induced bone marrow injury, which is ameliorated by a soluble Dll1 ligand through Csf2rb2 upregulation.
Disruption of Notch signaling aggravates irradiation-induced bone marrow injury, which is ameliorated by a soluble Dll1 ligand through Csf2rb2 upregulation.
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Notch 信号传导的破坏会加剧辐射引起的骨髓损伤，可溶性 Dll1 配体通过 Csf2rb2 上调可改善这种损伤
DOI：
10.1038/srep26003
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发表时间：
2016-05-18
影响因子：
4.6
通讯作者：
Han H
中科院分区：
文献类型：
--
作者：
Chen JJ;Gao XT;Yang L;Fu W;Liang L;Li JC;Hu B;Sun ZJ;Huang SY;Zhang YZ;Liang YM;Qin HY;Han H
物理和化学损伤诱导的骨髓（BM）损伤通常导致由造血干细胞和祖细胞（HSPC）耗竭和/或恶化的BM基质引起的致死性。Notch信号在造血过程中起重要作用，但其是否参与骨髓损伤尚不清楚。在这项研究中，我们发现，RBP-J，经典的Notch信号的转录因子的条件性中断，增加小鼠的辐射敏感性。用内皮细胞（EC）靶向的可溶性Dll 1 Notch配体mD 1 R激活Notch信号传导促进照射后的BM恢复。mD 1 R处理导致照射后BM、脾和外周血中的髓系祖细胞和单核细胞显著增加。mD 1 R还增强了环磷酰胺（一种诱导BM抑制的化疗药物）治疗小鼠的造血功能。mD 1 R可促进骨髓细胞增殖，减少骨髓细胞凋亡。β链细胞因子受体Csf 2 rb 2被鉴定为造血细胞中Notch信号传导的下游分子。mD 1 R通过上调Csf 2 rb 2的造血表达来改善造血恢复。我们的研究结果揭示了Notch信号在放射和药物诱导的BM抑制中的作用，并建立了一种新的潜在的治疗放疗和化疗诱导的BM和骨髓抑制的方法。
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.