Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Nat Immunol. 2011 May;12(5):391-8. doi: 10.1038/ni.2017. Epub 2011 Mar 27.
The chemokine CXCL12 is essential for the function of hematopoietic stem and progenitor cells. Here we report that secretion of functional CXCL12 from human bone marrow stromal cells (BMSCs) was a cell contact-dependent event mediated by connexin-43 (Cx43) and Cx45 gap junctions. Inhibition of connexin gap junctions impaired the secretion of CXCL12 and homing of leukocytes to mouse bone marrow. Purified human CD34(+) progenitor cells did not adhere to noncontacting BMSCs, which led to a much smaller pool of immature cells. Calcium conduction activated signaling by cAMP-protein kinase A (PKA) and induced CXCL12 secretion mediated by the GTPase RalA. Cx43 and Cx45 additionally controlled Cxcl12 transcription by regulating the nuclear localization of the transcription factor Sp1. We suggest that BMSCs form a dynamic syncytium via connexin gap junctions that regulates CXC12 secretion and the homeostasis of hematopoietic stem cells.
趋化因子 CXCL12 对于造血干细胞和祖细胞的功能至关重要。在这里，我们报告说，人骨髓基质细胞（BMSC）中功能性 CXCL12 的分泌是一种细胞接触依赖性事件，由连接蛋白-43（Cx43）和 Cx45 缝隙连接介导。缝隙连接连接蛋白的抑制会损害 CXCL12 的分泌和白细胞向小鼠骨髓的归巢。纯化的人 CD34(+)祖细胞不会附着在不接触的 BMSC 上，这导致未成熟细胞的数量大大减少。钙传导激活 cAMP-蛋白激酶 A（PKA）信号通路，并诱导由 GTPase RalA 介导的 CXCL12 分泌。Cx43 和 Cx45 还通过调节转录因子 Sp1 的核定位来控制 Cxcl12 转录。我们认为，BMSC 通过连接蛋白缝隙连接形成一个动态合胞体，调节 CXCL12 的分泌和造血干细胞的稳态。
