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

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

doi:10.1038/ni.2017

Cited by 153 publications

(126 citation statements)

References 50 publications

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“…Second, it has been shown that Cx43 mediates BM stromal cell adhesion to HSCs (29). To address whether the contact of HSCs with BM stromal cells was causal in the control of HSC ROS levels, we cocultured HSC/P cells derived from WT or H-Cx43-deficient mice with preplated FBMD-1 stromal cells, a wellrecognized model of heterocellular hematopoiesis-supporting stroma (30) composed of ROS high and ROS low cell populations (Fig.…”

Section: To Clarify Whethermentioning

confidence: 99%

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Ishikawa

González‐Nieto

Ghiaur

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

142

105

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Hematopoietic stem cell (HSC) aging has become a concern in chemotherapy of older patients. Humoral and paracrine signals from the bone marrow (BM) hematopoietic microenvironment (HM) control HSC activity during regenerative hematopoiesis. Connexin-43 (Cx43), a connexin constituent of gap junctions (GJs) is expressed in HSCs, down-regulated during differentiation, and postulated to be a self-renewal gene. Our studies, however, reveal that hematopoietic-specific Cx43 deficiency does not result in significant long-term competitive repopulation deficiency. Instead, hematopoietic Cx43 (H-Cx43) deficiency delays hematopoietic recovery after myeloablation with 5-fluorouracil (5-FU). 5-FU-treated H-Cx43-deficient HSC and progenitors (HSC/P) cells display decreased survival and fail to enter the cell cycle to proliferate. Cell cycle quiescence is associated with down-regulation of cyclin D1, up-regulation of the cyclin-dependent kinase inhibitors, p21 cip1. and p16 INK4a , and Forkhead transcriptional factor 1 (Foxo1), and activation of p38 mitogen-activated protein kinase (MAPK), indicating that H-Cx43-deficient HSCs are prone to senescence. The mechanism of increased senescence in H-Cx43-deficient HSC/P cells depends on their inability to transfer reactive oxygen species (ROS) to the HM, leading to accumulation of ROS within HSCs. In vivo antioxidant administration prevents the defective hematopoietic regeneration, as well as exogenous expression of Cx43 in HSC/P cells. Furthermore, ROS transfer from HSC/P cells to BM stromal cells is also rescued by reexpression of Cx43 in HSC/P. Finally, the deficiency of Cx43 in the HM phenocopies the hematopoietic defect in vivo. These results indicate that Cx43 exerts a protective role and regulates the HSC/P ROS content through ROS transfer to the HM, resulting in HSC protection during stress hematopoietic regeneration.

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Section: To Clarify Whethermentioning

confidence: 99%

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Ishikawa

González‐Nieto

Ghiaur

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

142

105

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“…Indeed, it was reported in various cell types that the absence of Cx43 leads to a differential cellular transcriptome, which ultimately determines phenotyp- ical changes in cell morphology and cell adhesion suggesting that Cx43 has a direct role on gene transcription (6). On the other hand, studies carried out in osteosarcoma cell lines and in mouse bone marrow stromal cells (BMSCs), have shown that defects in GJIC may alter the subcellular localization and the recruitment of transcription factors to the promoter region of certain genes, impacting upon gene transcription (52,53). In this case, it was hypothesized that differential GJ-mediated passage of second messengers modulates signaling pathways that will affect the binding affinity and/or activity of the transcription factor Sp1.…”

Section: Table III Interaction Of Cx43 With Hnrnps Varies In Ischemiamentioning

confidence: 99%

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Martins‐Marques

Anjo

Pereira

et al. 2015

Molecular & Cellular Proteomics

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The coordinated and synchronized cardiac muscle contraction relies on an efficient gap junction-mediated intercellular communication (GJIC) between cardiomyocytes, which involves the rapid anisotropic impulse propagation through connexin (Cx)-containing channels, namely of Cx43, the most abundant Cx in the heart. Expectedly, disturbing mechanisms that affect channel activity, localization and turnover of Cx43 have been implicated in several cardiomyopathies, such as myocardial ischemia. Besides gap junction-mediated intercellular communication, Cx43 has been associated with channel-independent functions, including modulation of cell adhesion, differentiation, proliferation and gene transcription. It has been suggested that the role played by Cx43 is dictated by the nature of the proteins that interact with Cx43. Therefore, the characterization of the Cx43-interacting network and its dynamics is vital to understand not only the molecular mechanisms underlying pathological malfunction of gap junction-mediated intercellular communication, but also to unveil novel and unanticipated biological functions of Cx43. In the present report, we applied a quantitative SWATH-MS approach to characterize the Cx43 interactome in rat hearts subjected to ischemia and ischemiareperfusion. Our results demonstrate that, in the heart, Cx43 interacts with proteins related with various biological processes such as metabolism, signaling and trafficking.

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“…Indeed, the gap junction protein connexin-43 has been shown to regulate HSPC homing and engraftment. While one study has shown that BM stromal CXCL12 secretion requires electromechanical coupling by connexin-43 and -45, 24 another study has shown that connexin-43 deficiency increases BM stromal CXCL12 secretion but it compromises HSC homing and hematopoietic recovery upon myeloablation. 25 This is at least partly due to connexin-43-mediated transfer of high, damaging amounts of reactive oxygen species to the BM stroma, which would protect HSCs during stress hematopoiesis.…”

Section: Autonomic Regulation Of Hematopoiesis and Cancermentioning

confidence: 99%

Autonomic regulation of hematopoiesis and cancer

Toro

Méndez-Ferrer

2013

Haematologica

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

Cited by 153 publications

References 50 publications

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Autonomic regulation of hematopoiesis and cancer

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