Xenotransplantation, that is, the transplantation of cells, tissues, and organs between species, is a rapidly developing alternative to classical transplantology in human medicine. Since the first successful kidney transplant in 1954, transplant medicine has made enormous progress. Until today, there are numerous patients worldwide waiting for an organ to be transplanted, and the number is still increasing, whereas the number of available organs is decreasing. One promising solution to this critical issue is the breeding of genetically modified animals as potential donors, which has gained the attention of scientists over the past two decades. Recent advancements in xenotransplantation have led to successful transfers of genetically modified pig organs into human recipients. Particularly, pig kidneys have been transplanted into living humans, demonstrating normal postsurgical function. Additionally, pig lungs functioned for 9 days in a brain-dead individual without experiencing hyperacute rejection. Furthermore, the successful xenotransplantation of pig hearts into living persons, exhibiting life-sustaining graft function, underscores significant progress toward clinically viable xenotransplants. This review provides an updated overview of the animal species and models used in xenotransplantation, with particular emphasis on the potential of transgenic pigs as donors. It discusses the process involved in producing the aforementioned animals, including the methods used to modify their genome. Particular attention is paid to immunological and genetic barriers, as well as zoonotic risks, and the possibilities and limitations of this technology. Although xenotransplantation is still in its experimental stage, it may play a crucial role in saving patients' lives in the future.
| [1] |
Barry JM, Murray JE. The first human renal transplants. J Urol. 2006;176:888-890.
|
| [2] |
Deng MC. Cardiac transplantation. Heart. 2002;87:177-184.
|
| [3] |
Starzl TE, Iwatsuki S, Van Thiel DH, et al. Evolution of liver transplantation. Hepatology. 1982;2:614S-636S.
|
| [4] |
Venuta F, Raemdonck DV. History of lung transplantation. J Thorac Dis. 2017;9:5458-5471.
|
| [5] |
Organ Donation Statistics. Organdonor.gov [Internet]. Accessed July 26, 2025. https://www.organdonor.gov/learn/organ-donation-statistics
|
| [6] |
Annual Presentation. Scandiatransplant [Internet]. Accessed July 26, 2025. https://www.scandiatransplant.org/resources/diasshow
|
| [7] |
Yearly Statistics. Eurotransplant [Internet]. Accessed July 26, 2025. https://www.eurotransplant.org/statistics/yearly-statistics/.
|
| [8] |
Cooper DK, Ekser B, Ramsoondar J, Phelps C, Ayares D. The role of genetically engineered pigs in xenotransplantation research. J Pathol. 2016;238:288-299.
|
| [9] |
Nowacka M. Etyka a Transplantacje. Wydawnictwo Naukowe PWN; 2003.
|
| [10] |
Gołąb J, Lasek W, Jakóbisiak M, Stokłosa T. Immunologia. 6th ed. Wydawnictwo Naukowe PWN; 2014.
|
| [11] |
Cozzi E, White DJG. The generation of transgenic pigs as potential organ donors for humans. Nat Med. 1995;1:964-966.
|
| [12] |
Cooper DKC, Hara H, Iwase H, et al. Clinical pig kidney xenotransplantation: how close are we? J Am Soc Nephrol. 2020;31:12-21.
|
| [13] |
Kim SC, Mathews DV, Breeden CP, et al. Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion. Am J Transplant. 2019;19:2174-2185.
|
| [14] |
Burdorf L, Laird CT, Harris DG, et al. Pig-to-baboon lung xenotransplantation: extended survival with targeted genetic modifications and pharmacologic treatments. Am J Transplant. 2022;22:28-45.
|
| [15] |
Groth CG. The potential advantages of transplanting organs from pig to man: a transplant surgeon's view. Indian J Urol. 2007;23:305-309.
|
| [16] |
Niemann H, Petersen B. The production of multi-transgenic pigs: update and perspectives for xenotransplantation. Transgenic Res. 2016;25:361-374.
|
| [17] |
El-Husseiny HM, Mady EA, Kaneda M, et al. Comparison of bovine- and porcine-derived decellularized biomaterials: promising platforms for tissue engineering applications. Pharmaceutics. 2023;15:1906.
|
| [18] |
Cooper DKC, Ezzelarab MB, Hara H, et al. The pathobiology of pig-to-primate xenotransplantation: a historical review. Xenotransplantation. 2016;23:83-105.
|
| [19] |
Ali A, Kurome M, Kessler B, Kemter E, Wolf E. What genetic modifications of source pigs are essential and sufficient for cell, tissue, and organ xenotransplantation? Transpl Int. 2024;37:13681.
|
| [20] |
Galli C. Current techniques of gene editing in pigs for xenotransplantation. Transpl Int. 2025;38:13807.
|
| [21] |
Xi J, Zheng W, Chen M, Zou Q, Tang C, Zhou X. Genetically engineered pigs for xenotransplantation: hopes and challenges. Front Cell Dev Biol. 2023;10:1-9.
|
| [22] |
Adams AB, Kim SC, Martens GR, et al. Xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival. Ann Surg. 2018;268:564-573.
|
| [23] |
Hinrichs A, Riedel EO, Klymiuk N, et al. Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies. Xenotransplantation. 2021;28:e12664.
|
| [24] |
Lange A, Medugorac I, Ali A, et al. Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation. Xenotransplantation. 2024;31:e12858.
|
| [25] |
Anand RP, Layer JV, Heja D, et al. Design and testing of a humanized porcine donor for xenotransplantation. Nature. 2023;622:393-401.
|
| [26] |
Koo OJ, Park HJ, Kwon DK, Kang JT, Jang G, Lee BC. Effect of recipient breed on delivery rate of cloned miniature pig. Zygote. 2009;17:203-207.
|
| [27] |
Swindle MM. Swine in the Laboratory: Surgery, Anesthesia, Imaging and Experimental Techniques. 2nd ed. CRC Press (Taylor and Francis); 2007.
|
| [28] |
Conn PM. Sourcebook of Models for Biomedical Research. Humana Press Inc.; 2008:778.
|
| [29] |
Pepper M, Gouveia C, Labuschaigne M. Legislation governing pluripotent stem cells in South Africa. S Afr J Bioeth Law. 2015;8:23.
|
| [30] |
Galli C, Lazzari G. 25th anniversary of cloning by somatic-cell nuclear transfer: current applications of SCNT in advanced breeding and genome editing in livestock. Reproduction. 2021;162:F23-F32.
|
| [31] |
Galli C. Animal engineering for xenotransplantation. Eur J Transplant. 2023;1:182-191.
|
| [32] |
Peterson L, Yacoub MH, Ayares D, et al. Physiological basis for xenotransplantation from genetically modified pigs to humans. Physiol Rev. 2024;104:1409-1459.
|
| [33] |
Ruan D, Peng J, Wang X, et al. XIST derepression in active X chromosome hinders pig somatic cell nuclear transfer. Stem Cell Reports. 2018;10:494-508.
|
| [34] |
Kishigami S, Mizutani E, Ohta H, et al. Significant improvement of mouse cloning technique by treatment with trichostatin A after somatic nuclear transfer. Biochem Biophys Res Commun. 2006;340:183-189.
|
| [35] |
Zhao J, Ross JW, Hao Y, et al. Significant improvement in cloning efficiency of an inbred miniature pig by histone deacetylase inhibitor treatment after somatic cell nuclear Transfer. Biol Reprod. 2009;81:525-530.
|
| [36] |
Boquest AC, Grupen CG, Harrison SJ, et al. Production of cloned pigs from cultured fetal fibroblast cells. Biol Reprod. 2002;66:1283-1287.
|
| [37] |
Cho S, Kim J, Park J, et al. Serial cloning of pigs by somatic cell nuclear transfer: restoration of phenotypic normality during serial cloning. Dev Dyn. 2007;236:3369-3382.
|
| [38] |
Wu H, Lian M, Lai L. Multiple gene modifications of pigs for overcoming obstacles of xenotransplantation. Natl Sci Open. 2023;2:20230030.
|
| [39] |
Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with engineered zinc finger nucleases. Nat Rev Genet. 2010;11:636-646.
|
| [40] |
Malzahn A, Lowder L, Qi Y. Plant genome editing with TALEN and CRISPR. Cell Biosci. 2017;7:21.
|
| [41] |
Li T, Huang S, Jiang WZ, et al. TAL nucleases (TALNs): hybrid proteins composed of TAL effectors and FokI DNA-cleavage domain. Nucleic Acids Res. 2011;39:359-372.
|
| [42] |
Boch J, Scholze H, Schornack S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326:1509-1512.
|
| [43] |
Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816-821.
|
| [44] |
Miyaoka Y, Mayerl SJ, Chan AH, Conklin BR. Detection and quantification of HDR and NHEJ induced by genome editing at endogenous gene loci using droplet digital PCR. In: Karlin-Neumann G, Bizouarn F, eds. Digital PCR: Methods and Protocols. Springer; 2018:349-362.
|
| [45] |
Chang HHY, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-Strand break repair. Nat Rev Mol Cell Biol. 2017;18:495-506.
|
| [46] |
Rees HA, Yeh W-H, Liu DR. Development of hRad51–Cas9 Nickase fusions that mediate HDR without double-stranded breaks. Nat Commun. 2019;10:2212.
|
| [47] |
Li P, Estrada JL, Burlak C, et al. Efficient generation of genetically distinct pigs in a single pregnancy using multiplexed single-guide RNA and carbohydrate selection. Xenotransplantation. 2015;22:20-31.
|
| [48] |
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533:420-424.
|
| [49] |
Xie J, Ge W, Li N, et al. Efficient Base editing for multiple genes and loci in pigs using base editors. Nat Commun. 2019;10:2852.
|
| [50] |
Klymiuk N, Böcker W, Schönitzer V, et al. First inducible transgene expression in porcine large animal models. FASEB J. 2012;26:1086-1099.
|
| [51] |
Kues WA, Schwinzer R, Wirth D, et al. Epigenetic silencing and tissue independent expression of a novel tetracycline inducible system in double-transgenic pigs. FASEB J. 2006;20:1200-1202.
|
| [52] |
Cowan PJ, Shinkel TA, Fisicaro N, et al. Targeting gene expression to endothelium in transgenic animals: a comparison of the human ICAM-2, PECAM-1 and endoglin promoters. Xenotransplantation. 2003;10:223-231.
|
| [53] |
Aigner B, Klymiuk N, Wolf E. Transgenic pigs for xenotransplantation: selection of promoter sequences for reliable transgene expression. Curr Opin Organ Transplant. 2010;15:201-206.
|
| [54] |
Ramsoondar J, Vaught T, Ball S, et al. Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation. 2009;16:164-180.
|
| [55] |
Dieckhoff B, Petersen B, Kues WA, Kurth R, Niemann H, Denner J. Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs. Xenotransplantation. 2008;15:36-45.
|
| [56] |
Ahrens HE, Petersen B, Herrmann D, et al. siRNA mediated knockdown of tissue factor expression in pigs for xenotransplantation. Am J Transplant. 2015;15:1407-1414.
|
| [57] |
Das S, Koyano-Nakagawa N, Gafni O, et al. Generation of human endothelium in pig embryos deficient in ETV2. Nat Biotechnol. 2020;38:297-302.
|
| [58] |
Wolf E, Reichart B, Moretti A, Laugwitz K-L. Designer pigs for xenogeneic heart transplantation and beyond. Dis Model Mech. 2023;16:dmm050177.
|
| [59] |
Garry DJ, Garry MG, Nakauchi H, et al. Allogeneic, xenogeneic, and exogenic hearts for transplantation. Methodist Debakey Cardiovasc J. 2025;21:92-99.
|
| [60] |
Brown JL, Voth JP, Person K, Low WC. A technological and regulatory review on human–animal chimera research: the current landscape of biology, law, and public opinion. Cell Transplant. 2023;32:09636897231183112.
|
| [61] |
Bourret R, Martinez E, Vialla F, Giquel C, Thonnat-Marin A, De Vos J. Human–animal chimeras: ethical issues about farming chimeric animals bearing human organs. Stem Cell Res Ther. 2016;7:87.
|
| [62] |
Loike JD, Kadish A. Ethical rejections of xenotransplantation? EMBO Rep. 2018;19:e46337.
|
| [63] |
Wu J, Platero-Luengo A, Sakurai M, et al. Interspecies chimerism with mammalian pluripotent stem cells. Cell. 2017;168:473-486. e15.
|
| [64] |
Gafni O, Weinberger L, Mansour AA, et al. Derivation of novel human ground state naive pluripotent stem cells. Nature. 2013;504:282-286.
|
| [65] |
Theunissen TW, Powell BE, Wang H, et al. Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell. 2014;15:471-487.
|
| [66] |
Theunissen TW, Friedli M, He Y, et al. Molecular criteria for defining the naive human pluripotent state. Cell Stem Cell. 2016;19:502-515.
|
| [67] |
Huang J, Wu J. Humanizing pig kidneys via chimeric complementation. Cell Res. 2024;34:189-190.
|
| [68] |
Deacon T, Schumacher J, Dinsmore J, et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nat Med. 1997;3:350-353.
|
| [69] |
Matsumoto S, Abalovich A, Wechsler C, Wynyard S, Elliott RB. Clinical benefit of islet xenotransplantation for the treatment of type 1 diabetes. EBioMedicine. 2016;12:255-262.
|
| [70] |
Li X, Wang Y, Yang H, Dai Y. Liver and hepatocyte transplantation: what can pigs contribute? Front Immunol. 2022;12:802692.
|
| [71] |
Godehardt AW, Tönjes RR. Xenotransplantation of decellularized pig heart valves—regulatory aspects in Europe. Xenotransplantation. 2020;27:e12609.
|
| [72] |
Yoon CH, Choi HJ, Kim MK. Corneal xenotransplantation: where are we standing? Prog Retin Eye Res. 2021;80:100876.
|
| [73] |
Lévêque X, Nerrière-Daguin V, Neveu I, Naveilhan P. Pig neural cells derived from foetal mesencephalon as cell source for intracerebral xenotransplantation. In: Costa C, Máñez R, eds. Xenotransplantation: Methods and Protocols. Humana Press; 2012:233-243.
|
| [74] |
Vadori M, Aron Badin R, Hantraye P, Cozzi E. Current status of neuronal cell xenotransplantation. Int J Surg. 2015;23:267-272.
|
| [75] |
Fink JS, Schumacher JM, Ellias SL, et al. Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant. 2000;9:273-278.
|
| [76] |
Matsumoto S, Abalovich A, Wynyard S, Carulla ME, Abalovich D. Patients' opinions 10 years after receiving encapsulated porcine islet xenotransplantation without immunosuppression. Xenotransplantation. 2023;30:e12798.
|
| [77] |
Kim MK, Hara H. Current status of corneal xenotransplantation. Int J Surg. 2015;23:255-260.
|
| [78] |
Oh JW, Yoon CH, Ryu JS, Kim KP, Kim MK. Proteomics analysis of aqueous humor and rejected graft in pig-to-non-human primate corneal xenotransplantation. Front Immunol. 2022;13:859929.
|
| [79] |
Lee S, Dohlman TH, Dana R. Immunology in corneal transplantation—from homeostasis to graft rejection. Transplant Rev. 2025;39:100909.
|
| [80] |
Choi SH, Yoon CH, Lee HJ, et al. Long-term safety outcome of systemic immunosuppression in pig-to-nonhuman primate corneal xenotransplantation. Xenotransplantation. 2018;25:e12442.
|
| [81] |
Booth C, Korossis SA, Wilcox HE, et al. Tissue engineering of cardiac valve prostheses I: development and histological characterization of an acellular porcine scaffold. J Heart Valve Dis. 2002;11:457-462.
|
| [82] |
Gallo M, Naso F, Poser H, et al. Physiological performance of a detergent decellularized heart valve implanted for 15 months in Vietnamese pigs: surgical procedure, follow-up, and explant inspection. Artif Organs. 2012;36:E138-E150.
|
| [83] |
Calafiore AM, Haverich A, Gaudino M, et al. Immunoreaction to xenogenic tissue in cardiac surgery: alpha-gal and beyond. Eur J Cardiothorac Surg. 2022;62:ezac115.
|
| [84] |
Persson M, Glaser N, Franco-Cereceda A, Nilsson J, Holzmann MJ, Sartipy U. Porcine vs bovine bioprosthetic aortic valves: long-term clinical results. Ann Thorac Surg. 2021;111:529-535.
|
| [85] |
Shin HJ, Kim WK, Kim JK, et al. Pericardial versus porcine valves for surgical aortic valve replacement. Korean Circ J. 2021;52:136-146.
|
| [86] |
Taghizadeh B, Ghavami L, Derakhshankhah H, et al. Biomaterials in valvular heart diseases. Front Bioeng Biotechnol. 2020;8:529244.
|
| [87] |
Griffith BP, Grazioli A, Singh AK, et al. Transplantation of a genetically modified porcine heart into a live human. Nat Med. 2025;31:589-598.
|
| [88] |
Flowers M, Paika S, Cooper DKC, Mayrovitz HN. Anatomical and physiological considerations for pig cardiac xenotransplantation. Xenotransplantation. 2025;32:e70049.
|
| [89] |
Gene-edited pig kidney gives living donor new lease on life. NYU Langone Health [Internet]. Accessed July 26, 2025. https://nyulangone.org/news/gene-edited-pig-kidney-gives-living-donor-new-lease-life
|
| [90] |
Zhang X, Li X, Yang Z, et al. A review of pig liver xenotransplantation: current problems and recent Progress. Xenotransplantation. 2019;26:e12497.
|
| [91] |
Tao K-S, Yang Z-X, Zhang X, et al. Gene-modified pig-to-human liver xenotransplantation. Nature. 2025;641:1029-1036.
|
| [92] |
He J, Shi J, Yang C, et al. Pig-to-human lung xenotransplantation into a brain-dead recipient. Nat Med. 2025;31:3388-3393.
|
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