Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling
Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling
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DOI：
10.1182/blood-2010-02-270876
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发表时间：
2010-07-29
期刊：
影响因子：
20.3
通讯作者：
Kahn, Mark L.
中科院分区：
文献类型：
--
作者：
Bertozzi, Cara C.;Schmaier, Alec A.;Kahn, Mark L.
虽然血小板在胚胎发育的小鼠中出现在10.5天，但这些细胞的胚胎作用尚未确定。血细胞中需要SYK-SLP-76信号通路来调节胚胎血液-淋巴管分离，但该调节通路的细胞类型和分子机制尚不清楚。在本研究中，我们证明，血小板调节淋巴管的发展直接与淋巴管内皮细胞通过C型凝集素样受体2（CLEC-2）受体相互作用。PODOPLANIN（PDPN）是一种在淋巴管内皮细胞表面表达的跨膜蛋白，在非造血细胞中需要用于血液-淋巴管分离。PDPN受体CLEC-2的遗传缺失消除了血小板对PDPN的结合，并赋予胚胎淋巴管缺陷，如在缺乏PDPN或SLP-76的动物中所见。血小板因子4-Cre介导的Slp-76缺失足以赋予淋巴管缺陷，从而鉴定血小板为其中需要SLP-76信号传导来调节淋巴管发育的细胞类型。与这些遗传发现一致，我们观察到体内和体外淋巴管内皮细胞表面上SLP-76依赖性血小板聚集体的形成。这些研究确定了血小板CLEC-2受体结合淋巴管内皮PDPN并激活SLP-76信号传导以调节胚胎血管发育的非止血途径。（血。2010; 116（4）：661-670）
Although platelets appear by embryonic day 10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK-SLP-76 signaling pathway is required in blood cells to regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. Platelet factor 4-Cre-mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76-dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development. (Blood. 2010; 116(4): 661-670)