Regulatory Sequences of the Porcine THBD Gene Facilitate Endothelial-Specific Expression of Bioactive Human Thrombomodulin in Single- and Multitransgenic Pigs

Abstract

The biological efficacy of hTM suggests that the (multi-)transgenic donor pigs described here have the potential to overcome coagulation incompatibilities in pig-to-primate xenotransplantation.

Transgenic Expression of Human Thrombomodulin Inhibits HMGB1-Induced Porcine Aortic Endothelial Cell Activation

“…Transgenic hTBM on porcine aortic endothelial cells (PAEC) prolonged the clotting time of human blood in vitro. 3 In vivo, hTBM expression on cardiac xenografts was associated with a delay in the development of thrombotic microangiopathy and/or consumptive coagulopathy. 4 In addition to its anticoagulant properties, TBM also attenuates inflammation through activated protein C-dependent and -independent mechanisms.…”

Transgenic Expression of Human CD46 on Porcine Endothelium

“…Transgenic expression of human thrombomodulin has indeed been shown to be a promising approach. 56 Little is known on the fibrinolytic system in xenotransplantation models. In a very early report, Jørgensen et al 30 showed activation of fibrinolysis in a model of rabbit kidney xenoperfusion.…”

Tissue Sampling Guides for Porcine Biomedical Models

“…The respective protocols are designed to fit the demands of the industrial standards of the pharmaceutical industry and toxicologic pathology. They have been developed based on extensive experiences in pig toxicopathology, in pathomorphological characterization of numerous genetically modified pig models, and in porcine animal model biobanking (Abbott 2015;Aigner et al 2010;Kemter et al 2012;Klymiuk et al 2013;Klymiuk et al 2012a;Klymiuk et al 2012b;Klymiuk et al 2012c;Renner et al 2010Renner et al , 2012Renner et al , 2013Streckel et al 2015;Wuensch et al 2014). The proposed sampling protocols are intended as general guidelines but not as requirements for the sampling of tissues in any porcine model.…”

“…Pigs are increasingly being used as disease models in translational medicine and as large animal model systems in surgery, transplantation research, and toxicologic pathology Gun and Kues 2014;Lunney 2007;Wuensch et al 2014). The growing popularity of porcine models in biomedical research is due to several advantageous similarities between pigs and human beings that cannot be reproduced adequately in classical rodent models .…”