Horizons in TransplantationExperimental transplantationHuman Endothelial Protein C Receptor Overexpression Protects Intraportal Islet Grafts in Mice

- Inflammation and coagulation destroy transplanted pancreatic islet cells.
- We created a transgenic mouse line that strongly expresses human EPCR.
- Transgenic islets were intraportally transplanted in syngeneic diabetic recipients.
- Transgenic islets had improved engraftment compared with WT grafts.
- This strategy may be required for successful islet cell transplantation.

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.