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

Amir Schajnovitz, Tomer Itkin, Gabriele D'Uva, Alexander Kalinkovich, Karin Golan, Aya Ludin, Dror Cohen, Ziv Shulman, Abraham Avigdor, Arnon Nagler, Orit Kollet, Rony Seger, Tsvee Lapidot*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)391-398
Number of pages8
JournalNature Immunology
Volume12
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Funding

FundersFunder number
European CommissionHEALTH-F5-2010-261387
Israel Science FoundationISF 544/09

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