title: Human Endothelial Protein C Receptor Overexpression Protects Intraportal Islet Grafts in Mice.
abstract: Islet transplantation can potentially cure type 1 diabetes mellitus, but it is limited by a shortage of human donors as well as by islet graft destruction by inflammatory and thrombotic mechanisms. A possible solution to these problems is to use genetically modified pig islets. Endothelial protein C receptor (EPCR) enhances protein C activation and regulates coagulation, inflammation, and apoptosis. We hypothesized that human EPCR (hEPCR) expression on donor islets would improve graft survival and function. Islets from an hEPCR transgenic mouse line strongly expressed the transgene, and hEPCR expression was maintained after islet isolation. Islets were transplanted from hEPCR mice and wild-type (WT) littermates into diabetic mice in a marginal-dose syngeneic intraportal islet transplantation model. The blood glucose level normalized within 5 days in 5 of 7 recipients of hEPCR islets, compared with only 2 of 7 recipients of WT islets (P < .05). Transplanted hEPCR islets had better preserved morphology and more intense insulin staining than WT grafts, and they retained transgene expression. The improved engraftment compared with WT islets suggests that inflammation and coagulation associated with the transplant process can be reduced by hEPCR expression on donor tissue.
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
authors: H
authors: H
authors: Gock
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
authors: K F E
authors: KF
authors: Lee
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
authors: L
authors: L
authors: Murray-Segal
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
authors: T B
authors: TB
authors: Mysore
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
authors: A J F
authors: AJ
authors: d'Apice
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
authors: E J
authors: EJ
authors: Salvaris
authors: Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia. Electronic address: peter.cowan@svha.org.au.
authors: P J
authors: PJ
authors: Cowan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000601:surgery*; D000074283:Endothelial Protein C Receptor; D006085:Graft Survival; D006801:Humans; D007328:Insulin / Q000032:analysis; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020011:Protective Agents / Q000378:metabolism; D011486:Protein C / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013552:Swine; D019737:Transplants / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D001786:Blood Glucose; D000074283:Endothelial Protein C Receptor; D007328:Insulin; C478370:PROCR protein, human; D020011:Protective Agents; D011486:Protein C; D011956:Receptors, Cell Surface