【进展|热点】Nature Immunology：骨髓基质细胞通过细胞间接触分泌SDF-1

Nature Immunology | Article 2011 Mar 27. [Epub ahead of print]


CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions


Amir Schajnovitz, et al.

1 Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

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.

文章简介：

CXCL12（SDF-1）对造血干细胞和前体细胞的功能发育至关重要，在骨髓中，骨髓基质细胞分泌CXCL12构成其主要来源。在骨髓造血微环境中，成骨细胞、其前体间充质干细胞、高表达CXCL12的网状细胞构成了基质细胞的主要细胞组分。

间充质干细胞（mesenchymal stem cell, MSC）高表答间隙连接蛋白Connexin-43和Connexin-45。本研究发现，骨髓基质细胞通过与间隙连接蛋白Connexin-43和Connexin-45介导的细胞间接触模式分泌功能型CXCL12。阻断间隙连接可破坏CXCL12的分泌和小鼠淋巴细胞向骨髓归巢，纯化的CD34+人造血前体细胞也无法与骨髓机制细胞结合，导致分化障碍。Connexin-43和Connexin-45联合作用与转录因子Sp1，调控CXCL12的转录。同时发现，钙离子通过PKA传到活化信号，诱导CXCL12的分泌。研究结果提示，骨髓基质细胞通过细胞间缝隙连接形成动态合体，调节CXCL12的分泌和造血干细胞的动态平衡。

本研究的意义：

深化了对骨髓基质细胞分泌CXCL12的认识。钙元素在细胞运动和成骨细胞骨化过程中及其重要，钙离子调节CXCL12表达的发现，也进一步说明钙离子在维持骨髓造血微环境中干细胞自紊平衡和骨髓基质细胞功能方面扮演重要角色。

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After being stimulated, individual BMSCs take up extracellular calcium (Ca²⁺) and transmit this across a network of BMSCs that are interconnected via Cx43-Cx45 gap junctions. The intercellular transmission of calcium sequentially activates signaling through cyclic AMP, protein kinase A and RalA that ultimately leads to higher expression and more secretion of CXCL12. HSCs can then be recruited to and maintained in the vicinity of this niche dependent on sustained expression and secretion of CXCL12 by BMSCs. This syncytium, composed of a network of BMSCs, may be disrupted in response to stress, such as by a direct effect on the expression of Cx43 and Cx45, as shown for G-CSF-induced mobilization. Consequently, calcium-mediated intercellular signal transduction is abrogated, resulting in lower expression and less secretion of CXCL12 in the niche. HSCs are no longer maintained in this environment and are therefore mobilized and/or are activated to generate more mature progeny.