title: Chemokine-mediated robust augmentation of liver engraftment: a novel approach.
abstract: Effective repopulation of the liver is essential for successful clinical hepatocyte transplantation. The objective was to improve repopulation of the liver with human hepatocytes using chemokines. We used flow cytometry and immunohistochemistry assays to identify commonly expressed chemokine receptors on human fetal and adult hepatocytes. The migratory capacity of the cells to various chemokines was tested. For in vivo studies, we used a nude mouse model of partial hepatectomy followed by intraparenchymal injections of chemokine ligands at various concentrations. Human fetal liver cells transformed with human telomerase reverse transcriptase were used for intrasplenic cell transplantation. Repopulation and functionality were assessed 4 weeks after transplantation. The receptor CXCR3 was commonly expressed on both fetal and adult hepatocytes. Both cell types migrated efficiently toward corresponding CXC chemokine ligands 9, 10, and 11. In vivo, animals injected with recombinant chemokines showed the highest cell engraftment compared with controls (p<.05). The engrafted cells expressed several human hepatic markers such as cytokeratin 8 and 18 and albumin as well as transferrin, UGT1A1, hepatocyte nuclear factor (1α, 1β, and 4α), cytochrome CYP3A1, CCAAT/enhancer binding protein (α and β), and human albumin compared with controls. No inflammatory cells were detected in the livers at 4 weeks after transplantation. The improved repopulation of transplanted cells is likely a function of the chemokines to mediate cell homing and retention in the injured liver and might be an attractive strategy to augment repopulation of transplanted hepatocytes in vivo.
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: Meghnad
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: Mihai
authors.initials: M
authors.lastname: Oltean
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: Pradeep B
authors.initials: PB
authors.lastname: Patil
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Hallberg
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: Marika
authors.initials: M
authors.lastname: Kleman
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Holgersson
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Olausson
authors.affiliation: Laboratory for Transplantation Biology and Regenerative Medicine, Department of Surgery, and Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; NovaHep AB, Stockholm, Sweden suchitra.holgersson@surgery.gu.se.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Sumitran-Holgersson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D022781:Hepatocytes / Q000637:transplantation*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000601:surgery*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018925:Chemokines
keywords: Cell migration; Fetal liver cells; Hepatocyte transplantation; Immunodeficient mouse; Preconditioning