Consistent success in life-supporting porcine cardiac xenotransplantation

Längin, Matthias; Mayr, Tanja; Reichart, Bruno; Michel, Sebastian; Buchholz, Stefan; Guethoff, Sonja; Dashkevich, Alexey; Baehr, Andrea; Egerer, Stefanie; Bauer, Andreas; Mihalj, Maks; Panelli, Alessandro; Issl, Lara; Ying, Jiawei; Fresch, Ann Kathrin; Buttgereit, Ines; Mokelke, Maren; Radan, Julia; Werner, Fabian; Lutzmann, I.; Steen, Stig; Sjöberg, Trygve; Paskevicius, Audrius; Liao, Qiuming; Sfriso, Riccardo; Rieben, Robert; Dahlhoff, Maik; Keßler, Barbara; Kemter, Elisabeth; Kurome, Mayuko; Zakhartchenko, Valeri; Klett, Katharina; Hinkel, Rabea; Kupatt, Christian; Falkenau, Almuth; Reu, Simone; Ellgass, Reinhard; Herzog, Rudolf; Binder, Uli; Wich, Günter; Skerra, Arne; Ayares, David; Kind, Alexander; Schönmann, Uwe; Kaup, Franz‐Josef; Hagl, Christian; Wolf, Eckhard; Klymiuk, Nikolai; Brenner, Paolo; Abicht, Jan‐Michael

doi:10.1038/s41586-018-0765-z

Cited by 351 publications

(402 citation statements)

References 23 publications

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“…In vivo, Mohiuddin and his colleagues reported several heterotopic (non‐life–supporting) heart grafts from GTKO.hCD46.hTBM functioning for more than a year . Recently, 6‐month survival of genetically identical pig grafts placed orthotopically in baboons has been reported by the Munich group . Life‐supporting pig kidney grafts have also functioned for several months in the absence of any features of rejection, thrombotic microangiopathy, or consumptive coagulopathy (Figure A) (with the recipients eventually requiring euthanasia for opportunistic systemic infections, but not for immune injury to the grafts) …”

Section: Expression Of Human Coagulation‐regulatory Proteinsmentioning

confidence: 99%

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Cooper

Hara

Iwase

et al. 2019

Xenotransplantation

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Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications. We suggest that a pig with nine genetic modifications (ie, currently available) will provide organs (initially kidneys and hearts) that would function for a clinically valuable period of time, for example, >12 months, after transplantation into patients with end‐stage organ failure. The national regulatory authorities, however, will likely require evidence, based on in vitro and/or in vivo experimental data, to justify the inclusion of each individual genetic modification in the pig. We provide data both from our own experience and that of others on the advantages of pigs in which (a) all three known carbohydrate xenoantigens have been deleted (triple‐knockout pigs), (b) two human complement‐regulatory proteins (CD46, CD55) and two human coagulation‐regulatory proteins (thrombomodulin, endothelial cell protein C receptor) are expressed, (c) the anti‐apoptotic and “anti‐inflammatory” molecule, human hemeoxygenase‐1 is expressed, and (d) human CD47 is expressed to suppress elements of the macrophage and T‐cell responses. Although many alternative genetic modifications could be made to an organ‐source pig, we suggest that the genetic manipulations we identify above will all contribute to the success of the initial clinical pig kidney or heart transplants, and that the beneficial contribution of each individual manipulation is supported by considerable experimental evidence.

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Section: Expression Of Human Coagulation‐regulatory Proteinsmentioning

confidence: 99%

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Cooper

Hara

Iwase

et al. 2019

Xenotransplantation

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117

123

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“…Despite tremendous progress in the field , xenotransplantation won’t become clinical routine until the remaining issues have been thoroughly addressed. Currently, hyperacute rejection can be successfully prevented by transgenic expression of human complement regulators and knocking out the gene of the 1,3 galactosyltransferase.…”

Section: Discussionmentioning

confidence: 99%

Expression of human thrombomodulin on porcine endothelial cells can reduce platelet aggregation but did not reduce activation of complement or endothelium – an experimental study

et al. 2020

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Summary Clinical xenotransplantation will only be feasible when present limitations can be controlled sufficiently. Activation of endothelium and complement as well as coagulopathy and thrombotic microangiopathy (TMA) is important barriers. Transgenic expression of hTBM on porcine endothelial cells is a reasonable approach to reduce activation of haemostasis. Endothelial cells from wild‐type pigs as well from pigs expressing hTBM alone or in combination with hCD46 and knockout of the alpha‐1,3,‐galactosyltransferase (GTKO) were perfused with platelet‐rich plasma in a microfluidic flow chamber. Platelet aggregation and activation, coagulation, complement and endothelial cell activation were assessed. Perfusion of wild‐type porcine aortic endothelial cells (PAEC) resulted in distinct platelet aggregation. Expression of hTBM in either mono‐transgenic or triple‐transgenic (GTKO/hCD46/hTBM) PAEC showed significantly reduced or absent platelet aggregation. Flow cytometric analysis of platelets showed an increased CD62P expression in wild‐type PAEC and significantly reduced expression in mono‐ or triple‐transgenic PAEC. Activation of coagulation measured by TAT occured in WT PAEC and was clearly reduced in hTBM and GTKO/hCD46/hTBM PAEC. Activation of complement and endothelial cells was only reduced in GTKO/hCD46/hTBM but not in PAEC expressing hTBM alone. Expression of hTBM was able to prevent activation of coagulation and platelet aggregation in mono‐ and triple‐transgenic PAEC, while activation of complement and endothelial cells was not reduced in mono‐transgenic PAEC.

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“…Längin et al . recently succeeded in generating pig hearts lacking galactose‐α1,3‐galactose epitopes and expressing human CD46 and thrombomodulin by genetic engineering technology, and these pig hearts survived for up to 945 days after transplantation into baboons. Another problem of xenotransplantation involves possible infection of humans by porcine endogenous retrovirus; however Niu et al .…”

Section: Reconstructing the Kidney In Animalsmentioning

confidence: 99%

From organoids to transplantable artificial kidneys

Naganuma

Nishinakamura

2019

Transpl Int

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Summary It is difficult to restore kidney function following chronic kidney damage. Although dialysis is currently used to treat patients with chronic kidney disease, it does not cure the disease, while severely restricting the patient's daily and social activities. Kidney transplantation is an alternative and curative therapy, but donor numbers remain limited. However, the generation of kidney organoids from human induced pluripotent stem cells represents an important recent advance in regenerative medicine. Kidney organoids are expected to be used for disease modeling and drug discovery, and may eventually be applicable for transplantation. In this review, we describe the current status of kidney organoids and discuss the hurdles that need to be overcome to generate transplantable artificial kidneys.

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Consistent success in life-supporting porcine cardiac xenotransplantation

Cited by 351 publications

References 23 publications

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Expression of human thrombomodulin on porcine endothelial cells can reduce platelet aggregation but did not reduce activation of complement or endothelium – an experimental study

From organoids to transplantable artificial kidneys

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