Browsing by Subject "Receptors, CXCR4"

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    Effects of three long-acting reversible contraceptive methods on HIV target cells in the human uterine cervix and peripheral blood.
    (Reproductive biology and endocrinology : RB&E, 2019-02) Li, Liping; Zhou, Jie; Wang, Weijia; Huang, Lina; Tu, Jiaoqin; Baiamonte, Lyndsey; Stark, Moselle; Mills, Mistie; Hope, Thomas J; Drobnis, Erma Z; Quayle, Alison J; Schust, Danny J

    Background

    Hormonal contraceptives, particularly depot medroxyprogesterone acetate (DMPA), have been reported to be associated with substantially enhanced HIV acquisition; however, the biological mechanisms of this risk remain poorly understood. We aimed to investigate the effects of different hormonal contraceptives on the expression of the HIV co-receptors, CXCR4 and CCR5, on female endocervical and peripheral blood T cells.

    Methods

    A total of 59 HIV-negative women were enrolled, including 15 initiating DMPA, 28 initiating a levonorgestrel-releasing intrauterine device (LNG-IUD) and 16 initiating an etonogestrel (ETG)-delivering vaginal ring. Peripheral blood and endocervical cytobrush specimens were collected at enrollment and 3-4 weeks after contraception initiation to analyze the expression of CXCR4 and CCR5, on CD4+ and CD8+ T cells using flow cytometry.

    Results

    Administration of DMPA increased the percentages of CD4+ and CD8+ T cells expressing CCR5 in the endocervix but not in the peripheral blood. Administration of the LNG-IUD or the ETG vaginal ring did not affect the percentages of T lymphocytes expressing CXCR4 or CCR5 in the female cervix or peripheral blood.

    Conclusions

    Increase in the percentage of endocervical T cells expressing CCR5 upon DMPA exposure provides a plausible biological explanation for the association between DMPA use and an elevated risk of HIV infection.
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    Human Cartilage-Derived Progenitors Resist Terminal Differentiation and Require CXCR4 Activation to Successfully Bridge Meniscus Tissue Tears.
    (Stem cells (Dayton, Ohio), 2019-01) Jayasuriya, Chathuraka T; Twomey-Kozak, John; Newberry, Jake; Desai, Salomi; Feltman, Peter; Franco, Jonathan R; Li, Neill; Terek, Richard; Ehrlich, Michael G; Owens, Brett D
    Meniscus injuries are among the most common orthopedic injuries. Tears in the inner one-third of the meniscus heal poorly and present a significant clinical challenge. In this study, we hypothesized that progenitor cells from healthy human articular cartilage (chondroprogenitor cells [C-PCs]) may be more suitable than bone-marrow mesenchymal stem cells (BM-MSCs) to mediate bridging and reintegration of fibrocartilage tissue tears in meniscus. C-PCs were isolated from healthy human articular cartilage based on their expression of mesenchymal stem/progenitor marker activated leukocyte cell adhesion molecule (ALCAM) (CD166). Our findings revealed that healthy human C-PCs are CD166+, CD90+, CD54+, CD106- cells with multilineage differentiation potential, and elevated basal expression of chondrogenesis marker SOX-9. We show that, similar to BM-MSCs, C-PCs are responsive to the chemokine stromal cell-derived factor-1 (SDF-1) and they can successfully migrate to the area of meniscal tissue damage promoting collagen bridging across inner meniscal tears. In contrast to BM-MSCs, C-PCs maintained reduced expression of cellular hypertrophy marker collagen X in monolayer culture and in an explant organ culture model of meniscus repair. Treatment of C-PCs with SDF-1/CXCR4 pathway inhibitor AMD3100 disrupted cell localization to area of injury and prevented meniscus tissue bridging thereby indicating that the SDF-1/CXCR4 axis is an important mediator of this repair process. This study suggests that C-PCs from healthy human cartilage may potentially be a useful tool for fibrocartilage tissue repair/regeneration because they resist cellular hypertrophy and mobilize in response to chemokine signaling. Stem Cells 2019;37:102-114.
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    Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.
    (J Hematol Oncol, 2018-03-04) Green, Michael MB; Chao, Nelson; Chhabra, Saurabh; Corbet, Kelly; Gasparetto, Cristina; Horwitz, Ari; Li, Zhiguo; Venkata, Jagadish Kummetha; Long, Gwynn; Mims, Alice; Rizzieri, David; Sarantopoulos, Stefanie; Stuart, Robert; Sung, Anthony D; Sullivan, Keith M; Costa, Luciano; Horwitz, Mitchell; Kang, Yubin
    BACKGROUND: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. METHODS: We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. RESULTS: Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. CONCLUSIONS: Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.
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    Selective enhancement of donor hematopoietic cell engraftment by the CXCR4 antagonist AMD3100 in a mouse transplantation model.
    (PLoS One, 2010-06-28) Kang, Yubin; Chen, Benny J; Deoliveira, Divino; Mito, Jeffrey; Chao, Nelson J
    The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation.
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    Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells.
    (Journal of vascular surgery, 2012-11) Zhang, Lisheng; Brian, Leigh; Freedman, Neil J

    Objective

    Because vein graft neointimal hyperplasia engenders vein graft failure, and because most vein graft neointimal cells derive from outside the vein graft, we sought to determine whether vein graft neointimal hyperplasia is affected by activity of the CXC chemokine receptor-4 (CXCR4), which is important for bone marrow-derived cell migration.

    Methods

    In congenic Cxcr4(-/+) and wild-type (WT) recipient mice, we performed interposition grafting of the common carotid artery with the inferior vena cava (IVC) of either Cxcr4(-/+) or WT mice to create four surgically chimeric groups of mice (n ≥ 5 each), characterized by vein graft donor/recipient: WT/WT; Cxcr4(-/+)/WT; WT/Cxcr4(-/+); and Cxcr4(-/+)/Cxcr4(-/+); vein grafts were harvested 6 weeks postoperatively.

    Results

    The agonist for CXCR4 is expressed by cells in the arterializing vein graft. Vein graft neointimal hyperplasia was reduced by reducing CXCR4 activity in vein graft-extrinsic cells, but not in vein graft-intrinsic cells: the rank order of neointimal hyperplasia was WT/WT ≈ Cxcr4(-/+)/WT > WT/Cxcr4(-/+) ≈ Cxcr4(-/+)/Cxcr4(-/+); CXCR4 deficiency in graft-extrinsic cells reduced neointimal hyperplasia by 39% to 47% (P < .05). Vein graft medial area was equivalent in all grafts except Cxcr4(-/+)/Cxcr4(-/+), in which the medial area was 60% ± 20% greater (P < .05). Vein graft re-endothelialization was indistinguishable among all three vein graft groups. However, the prevalence of medial leukocytes was 40% ± 10% lower in Cxcr4(-/+)/Cxcr4(-/+) than in WT/WT vein grafts (P < .05), and the prevalence of smooth muscle actin-positive cells was 45% ± 20% higher (P < .05).

    Conclusions

    We conclude that CXCR4 contributes to vein graft neointimal hyperplasia through mechanisms that alter homing to the vein graft of graft-extrinsic cells, particularly leukocytes.

    Clinical relevance

    The utility of autologous vein grafts is severely reduced by neointimal hyperplasia, which accelerates subsequent graft atherosclerosis. Our study demonstrates that vein graft neointimal hyperplasia is aggravated by activity of the cell-surface “CXC” chemokine receptor-4 (CXCR4), which is critical for recruitment of bone marrow-derived cells to sites of inflammation. Our model for CXCR4 deficiency used mice with heterozygous deficiency of Cxcr4. Consequently, our results suggest the possibility that a CXCR4 antagonist--like plerixafor, currently in clinical use--could be applied to vein grafts periadventitially, and perhaps achieve beneficial effects on vein graft neointimal hyperplasia.