title: CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions.
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.
authors: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors: Amir
authors: A
authors: Schajnovitz
authors: Tomer
authors: T
authors: Itkin
authors: Gabriele
authors: G
authors: D'Uva
authors: Alexander
authors: A
authors: Kalinkovich
authors: Karin
authors: K
authors: Golan
authors: Aya
authors: A
authors: Ludin
authors: Dror
authors: D
authors: Cohen
authors: Ziv
authors: Z
authors: Shulman
authors: Abraham
authors: A
authors: Avigdor
authors: Arnon
authors: A
authors: Nagler
authors: Orit
authors: O
authors: Kollet
authors: Rony
authors: R
authors: Seger
authors: Tsvee
authors: T
authors: Lapidot
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12 / Q000276:immunology*; D018920:Coculture Techniques; D017630:Connexins / Q000276:immunology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology; D017629:Gap Junctions / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D017154:Stromal Cells / Q000276:immunology*; D020725:ral GTP-Binding Proteins / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; D017630:Connexins; C515256:Cxcl12 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; C118120:Rala protein, mouse; D020725:ral GTP-Binding Proteins; D002118:Calcium