Protective effects of transgenic human endothelial protein C receptor expression in murine models of transplantation.
Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 μmol/L vs. 78.5 ± 10.0 μmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant-related thrombotic and inflammatory injury, without detrimental effects in the donor animal.
Immunology Research Centre, St. Vincent's Hospital, Melbourne, Australia.
K F E
KF
Lee
B
B
Lu
J C
JC
Roussel
L J
LJ
Murray-Segal
E J
EJ
Salvaris
S J
SJ
Hodgkinson
B M
BM
Hall
A J F
AJ
d'Apice
P J
PJ
Cowan
H
H
Gock
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000378:metabolism*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control
D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; C478370:PROCR protein, human; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface