ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking.
ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking.
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DOI：
10.1016/j.stemcr.2014.12.013
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发表时间：
2015-02-10
影响因子：
5.9
通讯作者：
Forsberg, E. Camilla
中科院分区：
文献类型：
--
作者：
Smith-Berdan, Stephanie;Nguyen, Andrew;Hong, Matthew A.;Forsberg, E. Camilla
尽管造血干细胞（hematopoietic stem cells，HSC）在临床治疗中的应用已经超过半个世纪，但调控HSC运输、植入和移植后终身存活的机制尚不清楚。在这里，我们表明，血管内皮细胞调节造血干细胞的运输进出骨髓（BM）壁龛。令人惊讶的是，我们发现血管内皮细胞不是作为细胞进入的屏障，而是通过引导分子ROBO 4积极促进HSC穿过血管壁易位到BM空间中。相反，我们发现血管系统抑制了逆转过程，因为诱导的血管通透性导致血流中HSC的快速增加。因此，血管内皮通过促进HSC从血液外渗到BM和通过形成防止BM逃逸到血液的血管屏障来加强HSC定位到BM小生境。我们的研究结果解开了调节HSC运输方向性的机制，并表明血管系统可以作为改善造血移植治疗的靶点。内皮ROBO 4促进HSC单向运输穿过血管壁窦状内皮细胞介导HSC从血液外渗到骨髓血管完整性防止HSC从骨髓逃逸到血液诱导的血管渗透性快速动员HSC进入血流造血干细胞（HSC）依赖于特定的骨髓环境以实现最佳的终身功能。在这个问题上，Forsberg及其同事证明，血管内皮细胞通过受体ROBO 4积极促进HSC从血流转移到骨髓，同时也防止HSC从骨髓逃逸。他们的发现解开了调控HSC贩运方向性的机制，并指出了操纵HSC位置的策略。
Despite the use of hematopoietic stem cells (HSCs) in clinical therapy for over half a century, the mechanisms that regulate HSC trafficking, engraftment, and life-long persistence after transplantation are unclear. Here, we show that the vascular endothelium regulates HSC trafficking into and out of bone marrow (BM) niches. Surprisingly, we found that instead of acting as barriers to cellular entry, vascular endothelial cells, via the guidance molecule ROBO4, actively promote HSC translocation across vessel walls into the BM space. In contrast, we found that the vasculature inhibits the reverse process, as induced vascular permeability led to a rapid increase in HSCs in the blood stream. Thus, the vascular endothelium reinforces HSC localization to BM niches both by promoting HSC extravasation from blood-to-BM and by forming vascular barriers that prevent BM-to-blood escape. Our results uncouple the mechanisms that regulate the directionality of HSC trafficking and show that the vasculature can be targeted to improve hematopoietic transplantation therapies. Endothelial ROBO4 promotes unidirectional HSC trafficking across vessel walls Sinusoidal endothelial cells mediate HSC extravasation from blood to bone marrow Vascular integrity prevents HSC escape from bone marrow to blood Induced vascular permeability rapidly mobilizes HSCs to the blood stream Hematopoietic stem cells (HSCs) depend on a specialized bone marrow environment for optimal life-long function. In this issue, Forsberg and colleagues demonstrate that the vascular endothelium, via the receptor ROBO4, actively promotes HSC translocation from the bloodstream to the bone marrow while also preventing HSC escape from the bone marrow. Their findings uncouple the mechanisms that regulate the directionality of HSC trafficking and point to strategies for manipulating HSC location.
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影响因子：
64.5
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通讯作者：
Kidd, T
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