title: Blockade of endothelial G(i) protein enhances early engraftment in intraportal cell transplant to mouse liver.
abstract: 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 G(i) 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 G(i) 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.
authors.affiliation: Cell Transplantation Unit, Department of Immunology Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Alfaro
authors.forename: Montserrat
authors.initials: M
authors.lastname: Grau
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Ana I
authors.initials: AI
authors.lastname: Checa
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Criado
authors.forename: Enrique
authors.initials: E
authors.lastname: Moreno
authors.forename: Estela
authors.initials: E
authors.lastname: Paz-Artal
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
authors.forename: Antonio
authors.initials: A
authors.lastname: Serrano
mesh_terms: D008841:Actin Cytoskeleton; D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go