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hEPCR.hTBM.hCD47.hHO‐1 with donor clodronate and DDAVP treatment improves perfusion and function of GalTKO.hCD46 porcine livers perfused with human blood

hEPCR.hTBM.hCD47.hHO‐1 with donor clodronate and DDAVP treatment improves perfusion and function... INTRODUCTIONLiver xenotransplantation is a possible solution to the shortage of human organs available. However, in addition to the well‐ recognized immunologic incompatibilities between humans and pigs, liver xenotransplantation suffers from other unique molecular challenges. Ex‐vivo perfusion studies utilizing porcine livers and human blood show rapid marked decreases in circulating platelets.1 In large animal models of in‐vivo liver xenotransplant, profound thrombocytopenia, physiologically inappropriate activation of the coagulation cascade and net consumption of coagulation pathway components are associated with a high incidence of hemorrhagic complications and short recipient survival in experiments using both wild‐type2 and transgenic pig livers.3 Notably, administration of exogenous coagulation factors yielded a significant survival benefit with GalTKO or GalTKO.hCD46 genetics, further supporting a role for coagulation pathway dysregulation as a critical barrier to clinical translation.4,5Thrombocytopenia in xenoliver models results from both platelet sequestration in the xenograft and a consumptive coagulopathy that includes circulating platelet activation and injury, leading to platelet scavenging in the recipient. Porcine Kupffer cells (liver‐resident macrophages) and liver sinusoidal endothelial cells (LSECs) are both shown to mediate physiologically inappropriate phagocytosis of human or baboon platelets.6,7 In addition, unlike human vWF, porcine vWF interacts constitutively with quiescent human platelets via glycoprotein Ib (GPIb) binding, leading http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

hEPCR.hTBM.hCD47.hHO‐1 with donor clodronate and DDAVP treatment improves perfusion and function of GalTKO.hCD46 porcine livers perfused with human blood

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References (51)

Publisher
Wiley
Copyright
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1111/xen.12731
Publisher site
See Article on Publisher Site

Abstract

INTRODUCTIONLiver xenotransplantation is a possible solution to the shortage of human organs available. However, in addition to the well‐ recognized immunologic incompatibilities between humans and pigs, liver xenotransplantation suffers from other unique molecular challenges. Ex‐vivo perfusion studies utilizing porcine livers and human blood show rapid marked decreases in circulating platelets.1 In large animal models of in‐vivo liver xenotransplant, profound thrombocytopenia, physiologically inappropriate activation of the coagulation cascade and net consumption of coagulation pathway components are associated with a high incidence of hemorrhagic complications and short recipient survival in experiments using both wild‐type2 and transgenic pig livers.3 Notably, administration of exogenous coagulation factors yielded a significant survival benefit with GalTKO or GalTKO.hCD46 genetics, further supporting a role for coagulation pathway dysregulation as a critical barrier to clinical translation.4,5Thrombocytopenia in xenoliver models results from both platelet sequestration in the xenograft and a consumptive coagulopathy that includes circulating platelet activation and injury, leading to platelet scavenging in the recipient. Porcine Kupffer cells (liver‐resident macrophages) and liver sinusoidal endothelial cells (LSECs) are both shown to mediate physiologically inappropriate phagocytosis of human or baboon platelets.6,7 In addition, unlike human vWF, porcine vWF interacts constitutively with quiescent human platelets via glycoprotein Ib (GPIb) binding, leading

Journal

Xenotransplantation – Wiley

Published: Mar 1, 2022

Keywords: ex‐vivo perfusion; liver xenotransplantation; transgenic pigs

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