CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice

Wilson, Gregory C.; Freeman, Christopher M.; Kuethe, Joshua W.; Quillin, rd Ralph C.; Nojima, Hiroyuki; Schuster, Rebecca; Blanchard, John; Edwards, Michael J.; Caldwell, Charles C.; Lentsch, Alex B.

doi:10.1152/ajpgi.00257.2014

Cited by 27 publications

(35 citation statements)

References 34 publications

(46 reference statements)

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“…Injection of AMD3100, a specific inhibitor of CXCR4, worsened ALI after CCl4 injection, providing additional clues to the hepatoprotective role of this axis through the recruitment of MSC from bone marrow to the injured liver [31]. In contrast, injection of AMD3100 resulted in increased hepatocyte proliferation and reduced necrosis after reperfusion in an ischemia-reperfusion injury mouse model, suggesting a specific mechanism following oxygen deprivation [32]. Serum CXCL12 levels were higher for every etiology in our cohort, consolidating the idea that CXCL12 is a major liver homeostatic chemokine.…”

Section: Discussionmentioning

confidence: 96%

“…Little is known concerning the role of CXCL10, CXCL11, CXCL12, and CXCL14 in human ALI, although their expression has been reported in many in vivo animal models of ALI and they have been shown to play important roles in human chronic liver diseases [27][28][29][30][31][32][33]. Here we aimed to provide evidence for the presence of these circulating chemokines during human ALI and to identify distinct chemokine expression patterns in ALI patients with various etiologies to propose new biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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Serum CXCL10, CXCL11, CXCL12 and CXCL14 chemokine patterns in patients with acute liver injury

Chalin¹,

Lefevre²,

Devisme³

et al. 2018

Journal of Hepatology

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Background & Aims: The chemokines CXCL10 (interferon ϒ-inducible protein 10 [IP-10]), CXCL11 (Human interferon inducible T cell alpha chemokine [I-TAC]), CXCL12 (stromal cell derived factor 1 [SDF-1]), and CXCL14 (breast and kidney-expressed chemokine [BRAK]) are involved in cell recruitment, migration, activation, and homing in liver diseases and have been shown to be upregulated during acute liver injury in animal models. However, their expression in patients with acute liver injury is unknown. Here, we aimed to provide evidence of the presence of circulating CXCL10, CXCL11, CXCL12, and CXCL14 during human acute liver injury to propose new inflammation biomarkers for acute liver injury. Methods: We analyzed the serum concentration of the studied chemokines in healthy donors (n=36) and patients (n=163) with acute liver injuries of various etiologies. Results: Serum CXCL10, CXCL11 and CXCL12 levels were elevated in all the studied groups except biliary diseases for CXCL11. CXCL14 was associated with only acute viral infection and vascular etiologies. The strongest correlation was found between the IFN-inducible studied chemokines (CXCL10 and CXCL11) in all patients and more specifically in the acute viral infection group. Conclusion: These data provide evidence for the presence of circulating CXCL10, CXCL11, CXCL12, and CXCL14 during acute liver injury and are consistent with data obtained in animal models. CXCL10, CXCL11 and CXCL12 were the most highly represented and CXCL14 the least represented chemokines. Differential expression patterns were obtained depending on acute liver injury etiology, suggesting the potential use of these chemokines as acute liver injury biomarkers.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Serum CXCL10, CXCL11, CXCL12 and CXCL14 chemokine patterns in patients with acute liver injury

Chalin¹,

Lefevre²,

Devisme³

et al. 2018

Journal of Hepatology

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“…In ischemic liver injury stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptor CXC chemokine receptor-4 (CXCR4) is used [134]. After right lobe hepatoctomy, for normal regeneration levels of hepatocyte growth factor (HGF), interleukin (IL) 6, tumor necrosis factor α (TNF-α), thrombopoietin (TPO), transforming growth factor β1 (TGF-β1), interferon (IFN) α, and IFNγ are to be normalized [135]. Similarly, partial hepatectomy, both NK cells and IFN-γ were required for BMDH generation [136].…”

Section: Therapeutic Role Of Cell Secreted Growth Factorsmentioning

confidence: 99%

Stem Cell Therapeutics of Acute Liver Diseases, Transplantation, and Regeneration

Upadhyay¹

2017

J Cell Sci Ther

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Present review article explains various causes of acute liver diseases and their therapeutics. This article describes major reasons of hepatic pathophysiological conditions and diseases including hepatitis, cholestasis, alcoholic and non-alcoholic steatohepatitis, jaundice, liver cirrhosis, carcinogenesis and many others. This article emphasizes use of proliferating hepatocytes, hepatic oval cells, adult human liver mesenchymal stem/progenitor cells, induced pluripotent stem cells (iPSCs) and hematopoietic stem cells in cell transplantation for restoration of liver structure and function. It also justified the therapeutic role of cell secreted growth factors and dietary factors required during natural healing and regeneration liver after surgery or liver transplantation. It sketches out regulatory roles of signaling pathways, expression of cell cycle regulators, growth factors, cytokines, and role of different mitogens in induction of liver stem/progenitor cells (LSPCs) after organ/stem cell transplantation. This article suggests a need for development of new advanced biomaterials, methods, technologies and stem cells for development of targeted therapies to combat and cure liver related diseases and disorders. This article also advice people for avoiding excessive use of alcohol, drugs, fats, salt, high energy diets, and iron as all are responsible of liver cirrhosis, damage and failure.

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“…Previous studies show that SDF-1 expression increases in the liver with ischemia/reperfusion (I/R) injury (Lentsch et al, 1999;Wilson et al, 2015). Our immunohistochemistry for SDF-1 in the mouse liver with ischemia/reperfusion (I/R) injury shows a significantly higher SDF-1level…”

Section: Resultsmentioning

confidence: 47%

“…Therefore the SDF-1 in the blood with an injured organ is modelled using the function form associated with modified-biexponential decay (Wilson et al, 2015):…”

Section: Model Formulationmentioning

confidence: 99%

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Supplemental Information 1: Supplemental Information

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Background. Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. Methods. A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. Results. Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1level in the I/R injured liver than that in the control. Correspondingly, the ELISA results illustrate a higher MSC dose in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ELISA results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. Discussion. The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveals the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs, especially under hypoxic preconditioning. The impact of the liver and MSC conditions on passive homing is small. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.

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CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice

Cited by 27 publications

References 34 publications

Serum CXCL10, CXCL11, CXCL12 and CXCL14 chemokine patterns in patients with acute liver injury

Serum CXCL10, CXCL11, CXCL12 and CXCL14 chemokine patterns in patients with acute liver injury

Stem Cell Therapeutics of Acute Liver Diseases, Transplantation, and Regeneration

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