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

doi:10.1038/ni.2017

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

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	391–398
Number of pages	8
Journal	Nature Immunology
Volume	12
Issue number	5
DOIs	https://doi.org/10.1038/ni.2017
State	Published - May 2011

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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10.1038/ni.2017

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Schajnovitz, A., Itkin, T., D'Uva, G., Kalinkovich, A., Golan, K., Ludin, A., Cohen, D., Shulman, Z., Avigdor, A., Nagler, A., Kollet, O., Seger, R., & Lapidot, T. (2011). CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. Nature Immunology, 12(5), 391–398. https://doi.org/10.1038/ni.2017

@article{a981466dc3db46c2b04551b5c7bb81ef,

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.",

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

note = "Israeli Science Foundation [ISF 544/09]; European Union [HEALTH-F5-2010-261387]; Edith Arnoff Stein Professorial Chair in Stem Cell ResearchWe thank J. Von Maltzen and K. Willecke (Institute of Genetics Division of Molecular Genetics, University of Bonn, Bonn, Germany) for BMSCs with loxP-flanked Cx45 that express Cre from the myxovirus promoter; G. Lalli (King's College London) for plasmids encoding Myc tag alone or Myc-tagged dominant negative RalA; M. Segal for helping with real-time calcium imaging; R. Alon, N. Dekel and I. H. Oh for discussions; and C. M. Sorensen for advice on connexin mimetic peptides. Supported by the Israeli Science Foundation (ISF 544/09), the European Union (Advance Cell-based Therapies for the Treatment of Primary Immunodeficiency HEALTH-F5-2010-261387) and The Edith Arnoff Stein Professorial Chair in Stem Cell Research (T. L.).",

year = "2011",

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doi = "10.1038/ni.2017",

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pages = "391–398",

journal = "Nature Immunology",

issn = "1529-2908",

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Schajnovitz, A, Itkin, T, D'Uva, G, Kalinkovich, A, Golan, K, Ludin, A, Cohen, D, Shulman, Z, Avigdor, A, Nagler, A, Kollet, O, Seger, R & Lapidot, T 2011, 'CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions', Nature Immunology, vol. 12, no. 5, pp. 391–398. https://doi.org/10.1038/ni.2017

TY - JOUR

T1 - CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions

AU - Schajnovitz, Amir

AU - Itkin, Tomer

AU - D'Uva, Gabriele

AU - Kalinkovich, Alexander

AU - Golan, Karin

AU - Ludin, Aya

AU - Cohen, Dror

AU - Shulman, Ziv

AU - Avigdor, Abraham

AU - Nagler, Arnon

AU - Kollet, Orit

AU - Seger, Rony

AU - Lapidot, Tsvee

N1 - Israeli Science Foundation [ISF 544/09]; European Union [HEALTH-F5-2010-261387]; Edith Arnoff Stein Professorial Chair in Stem Cell ResearchWe thank J. Von Maltzen and K. Willecke (Institute of Genetics Division of Molecular Genetics, University of Bonn, Bonn, Germany) for BMSCs with loxP-flanked Cx45 that express Cre from the myxovirus promoter; G. Lalli (King's College London) for plasmids encoding Myc tag alone or Myc-tagged dominant negative RalA; M. Segal for helping with real-time calcium imaging; R. Alon, N. Dekel and I. H. Oh for discussions; and C. M. Sorensen for advice on connexin mimetic peptides. Supported by the Israeli Science Foundation (ISF 544/09), the European Union (Advance Cell-based Therapies for the Treatment of Primary Immunodeficiency HEALTH-F5-2010-261387) and The Edith Arnoff Stein Professorial Chair in Stem Cell Research (T. L.).

PY - 2011/5

Y1 - 2011/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79955023043&partnerID=8YFLogxK

U2 - 10.1038/ni.2017

DO - 10.1038/ni.2017

M3 - مقالة

SN - 1529-2908

VL - 12

SP - 391

EP - 398

JO - Nature Immunology

JF - Nature Immunology

IS - 5

ER -

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

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