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Open Access Blockade of Endothelial Gi Protein Enhances Early Engraftment in Intraportal Cell Transplant to Mouse Liver

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The limited availability of liver donors and recent progress in cell therapy technologies has centered interest on cell transplantation as a therapeutic alternative to orthotopic liver transplant for restoring liver function. Following transplant by intraportal perfusion, the main obstacle to cell integration in the parenchyma is the endothelial barrier. Transplanted cells form emboli in the portal branches, inducing ischemia and reperfusion injury, which cause disruption of endothelial impermeability and activate the immune system. Approximately 95% of transplanted cells fail to implant and die within hours by anoikis or are destroyed by the host immune system. Intravascular perfusion of Bordetella pertussis toxin (PTx) blocks endothelial Gi proteins and acts as a reversible inducer of actin cytoskeleton reorganization, leading to interruption of cell confluence in vitro and increased vascular permeability in vivo. PTx treatment of the murine portal vascular tree 2 h before intraportal perfusion of embryonic stem cells facilitated rapid cell engraftment. By 2 h postperfusion, the number of implanted cells in treated mice was more than fivefold greater than in untreated controls, a difference that was maintained to at least 30 days posttransplant. We conclude that prior to cell transplant, PTx blockade of the Gi protein pathway in liver endothelium promotes rapid, efficient cell implantation in liver parenchyma, and blocks chemokine receptor signaling, an essential step in early activation of the immune system.

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Keywords: Drug effects; Hepatocyte transplant; Vascular endothelium

Document Type: Research Article

Affiliations: Cell Transplantation Unit, Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain

Publication date: 2012-07-01

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

    Cell Transplantation is now being published by SAGE. Please visit their website for the most recent issues.

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