Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution.
Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution.
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DOI：
10.1038/s41467-021-27263-y
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发表时间：
2021-11-30
影响因子：
16.6
通讯作者：
Chute JP
中科院分区：
文献类型：
--
作者：
Termini CM;Pang A;Fang T;Roos M;Chang VY;Zhang Y;Setiawan NJ;Signaevskaia L;Li M;Kim MM;Tabibi O;Lin PK;Sasine JP;Chatterjee A;Murali R;Himburg HA;Chute JP
电离辐射和化疗耗尽造血干细胞并损害造血干细胞所在的血管龛。造血干细胞再生需要来自完整骨髓（BM）血管生态位的信号，但控制BM血管生态位再生的机制知之甚少。我们报告说，骨髓血管内皮细胞分泌脑信号蛋白3A（SEMA 3A）在骨髓消融和SEMA 3A诱导p53介导的细胞凋亡，通过其受体，神经纤毛蛋白1（NRP 1），并激活细胞周期蛋白依赖性激酶5的信号转导。Nrp 1或Sema 3a的内皮细胞特异性缺失或抗NRP 1抗体的施用抑制BM内皮细胞凋亡，加速BM血管再生，并一致地驱动照射小鼠中的造血重建。响应于NRP 1抑制，BM内皮细胞增加Wnt信号放大蛋白R spondin 2的表达和分泌。抗Rspondin 2的全身给药阻断HSC再生和造血重建，否则这将响应于NRP 1抑制而发生。骨髓抑制后SEMA 3A-NRP 1信号传导促进BM血管消退，BM内皮细胞中SEMA 3A-NRP 1信号传导的治疗性阻断加速体内血管和造血再生。电离辐射和化学疗法耗尽造血干细胞，破坏血管生态位。在这里，作者表明辐射诱导骨髓内皮细胞（EC）分泌SEMA 3A，通过NRP 1诱导EC凋亡，NRP 1抑制促进血管再生和R spondin 2依赖性造血再生。
Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 – mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell – specific deletion of Nrp1 or Sema3a or administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A – NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A – NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo. Ionizing radiation and chemotherapy deplete haematopoietic stem cells and damage the vascular niche. Here the authors show that irradiation induces SEMA3A secretion from bone marrow endothelial cells (ECs), inducing EC apoptosis via NRP1 and that NRP1 inhibition promotes vascular regeneration and R spondin 2 dependent hematopoietic regeneration.
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影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
82.9
作者：
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影响因子：
10.5
作者：
de Lau W;Peng WC;Gros P;Clevers H
通讯作者：
Clevers H
影响因子：
21.3
作者：
Asada N;Kunisaki Y;Pierce H;Wang Z;Fernandez NF;Birbrair A;Ma'ayan A;Frenette PS
通讯作者：
Frenette PS
影响因子：
23.9
作者：
Chen, Qi;Liu, Yang;Adams, Ralf H.
通讯作者：
Adams, Ralf H.