Sphingosine-1-Phosphate Receptor-3 Supports Hematopoietic Stem and Progenitor Cell Residence Within the Bone Marrow Niche.
Sphingosine-1-Phosphate Receptor-3 Supports Hematopoietic Stem and Progenitor Cell Residence Within the Bone Marrow Niche.
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DOI：
10.1002/stem.2556
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Botchwey EA
中科院分区：
文献类型：
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作者：
Ogle ME;Olingy CE;Awojoodu AO;Das A;Ortiz RA;Cheung HY;Botchwey EA
造血干细胞和祖细胞（HSPCs）从骨髓中流出，在稳态过程中，并在压力增加的速度，然而，调节其贩运的机制仍然不完全清楚。在这里，我们描述了一个新的作用，脂质受体，鞘氨醇-1-磷酸受体3（S1 PR 3），在HSPC居住在骨髓龛。与分化的骨髓细胞相比，HSPC表达增加的S1 PR 3水平。药理学拮抗或敲除S1 PR 3动员HSPCs进入血液循环，表明S1 PR 3影响生态位定位。S1 PR 3拮抗作用抑制骨髓和血浆SDF-1，使HSPC能够向富含S1 P的血浆迁移。动员与AMD 3100介导的CXCR 4拮抗作用协同作用，CXCR 4将HSPC束缚在生态位中，并恢复了AMD 3100处理的移植物的归巢缺陷。S1 PR 3拮抗剂联合AMD 3100改善了致死性照射受者的再植入和存活率。我们的研究表明，S1 PR 3和CXCR 4信号合作，以维持HSPCs在生态位内的稳态。这些结果突出了S1 PR 3在HSPC生态位占据和运输中的重要作用，其可用于快速临床干细胞动员和再植入策略，以及设计用于通过生物活性脂质信号传导控制募集、归巢和定位的新型治疗剂的机会。
Hematopoietic stem and progenitor cells (HSPCs) egress from bone marrow during homeostasis and at increased rates during stress; however, the mechanisms regulating their trafficking remain incompletely understood. Here we describe a novel role for lipid receptor, sphingosine-1-phosphate receptor 3 (S1PR3), in HSPC residence within the bone marrow niche. HSPCs expressed increased levels of S1PR3 compared to differentiated bone marrow cells. Pharmacological antagonism or knockout of S1PR3 mobilized HSPCs into blood circulation, suggesting that S1PR3 influences niche localization. S1PR3 antagonism suppressed bone marrow and plasma SDF-1, enabling HSPCs to migrate towards S1P-rich plasma. Mobilization synergized with AMD3100-mediated antagonism of CXCR4, which tethers HSPCs in the niche, and recovered homing deficits of AMD3100-treated grafts. S1PR3 antagonism combined with AMD3100 improved re-engraftment and survival in lethally irradiated recipients. Our studies indicate that S1PR3 and CXCR4 signaling cooperate to maintain HSPCs within the niche under homeostasis. These results highlight an important role for S1PR3 in HSPC niche occupancy and trafficking that can be harnessed for both rapid clinical stem cell mobilization and re-engraftment strategies, as well as the opportunity to design novel therapeutics for control of recruitment, homing, and localization through bioactive lipid signaling.