1932

Abstract

End-stage organ failure can result from various preexisting conditions and occurs in patients of all ages, and organ transplantation remains its only treatment. In recent years, extensive research has been done to explore the possibility of transplanting animal organs into humans, a process referred to as xenotransplantation. Due to their matching organ sizes and other anatomical and physiological similarities with humans, pigs are the preferred organ donor species. Organ rejection due to host immune response and possible interspecies infectious pathogen transmission have been the biggest hurdles to xenotransplantation's success. Use of genetically engineered pigs as tissue and organ donors for xenotransplantation has helped to address these hurdles. Although several preclinical trials have been conducted in nonhuman primates, some barriers still exist and demand further efforts. This review focuses on the recent advances and remaining challenges in organ and tissue xenotransplantation.

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2024-02-15
2024-04-22
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Literature Cited

  1. 1.
    Hu X, Geng Z, Gonelle-Gispert C, Hawthrone WJ, Deng S, Buhler L. 2022. International human xenotransplantation inventory: a 10-year follow-up. Transplantation 106:1713–16
    [Google Scholar]
  2. 2.
    Eurotransplant 2023. Statistics Report Laboratory https://statistics.eurotransplant.org/
  3. 3.
    Cooper DK, Ekser B, Ramsoondar J, Phelps C, Ayares D. 2016. The role of genetically engineered pigs in xenotransplantation research. J. Pathol. 238:288–99
    [Google Scholar]
  4. 4.
    Sykes M, Sachs DH. 2022. Progress in xenotransplantation: overcoming immune barriers. Nat. Rev. Nephrol. 18:745–61
    [Google Scholar]
  5. 5.
    Denner J. 2021. Porcine endogenous retroviruses and xenotransplantation, 2021. Viruses 13:2156
    [Google Scholar]
  6. 6.
    Sykes M, Sachs DH. 2019. Transplanting organs from pigs to humans. Sci. Immunol. 4:eaau6298
    [Google Scholar]
  7. 7.
    Zhou Q, Li T, Wang K, Zhang Q, Geng Z et al. 2022. Current status of xenotransplantation research and the strategies for preventing xenograft rejection. Front. Immunol. 13:928173
    [Google Scholar]
  8. 8.
    Cowan PJ. 2022. Transgenic pigs for islet xenotransplantation. Pancreas and Beta Cell Replacement WJ Hawthorne 153–66 London: Academic
    [Google Scholar]
  9. 9.
    Byrne GW, McGregor CG, Breimer ME. 2015. Recent investigations into pig antigen and anti-pig antibody expression. Int. J. Surg. 23:223–28
    [Google Scholar]
  10. 10.
    Chinnuswami R, Hussain A, Loganathan G, Narayanan S, Porter GD, Balamurugan AN 2020. Porcine islet cell xenotransplantation. Xenotransplantation: Comprehensive Study S Miyagawa London: IntechOpen
    [Google Scholar]
  11. 11.
    Yan L-l, Ye L-p, Chen Y-h, He S-q, Zhang C-y et al. 2022. The influence of microenvironment on survival of intraportal transplanted islets. Front. Immunol. 13:849580
    [Google Scholar]
  12. 12.
    Tjernberg J, Ekdahl KN, Lambris JD, Korsgren O, Nilsson B. 2008. Acute antibody-mediated complement activation mediates lysis of pancreatic islets cells and may cause tissue loss in clinical islet transplantation. Transplantation 85:1193–99
    [Google Scholar]
  13. 13.
    Zhou H, Hara H, Cooper DK. 2019. The complex functioning of the complement system in xenotransplantation. Xenotransplantation 26:e12517
    [Google Scholar]
  14. 14.
    Lu T-Y, Xu X-L, Du X-G, Wei J-H, Yu J-N et al. 2022. Advances in innate immunity to overcome immune rejection during xenotransplantation. Cells 11:3865
    [Google Scholar]
  15. 15.
    Reichart B, Cooper DK, Längin M, Tönjes RR, Pierson RN III, Wolf E 2022. Cardiac xenotransplantation: from concept to clinic. Cardiovasc. Res. 118:3499–516
    [Google Scholar]
  16. 16.
    Kemter E, Denner J, Wolf E. 2018. Will genetic engineering carry xenotransplantation of pig islets to the clinic?. Curr. Diab. Rep. 18:103
    [Google Scholar]
  17. 17.
    Wolf E, Kemter E, Klymiuk N, Reichart B. 2019. Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation. Anim. Front. 9:13–20
    [Google Scholar]
  18. 18.
    Phelps CJ, Koike C, Vaught TD, Boone J, Wells KD et al. 2003. Production of α1,3-galactosyltransferase-deficient pigs. Science 299:411–14
    [Google Scholar]
  19. 19.
    Martens GR, Reyes LM, Butler JR, Ladowski JM, Estrada JL et al. 2017. Humoral reactivity of renal transplant-waitlisted patients to cells from GGTA1/CMAH/B4GalNT2, and SLA class I knockout pigs. Transplantation 101:e86–92
    [Google Scholar]
  20. 20.
    Diamond LE, Quinn CM, Martin MJ, Lawson J, Platt JL, Logan JS. 2001. A human CD46 transgenic pig model system for the study of discordant xenotransplantation. Transplantation 71:132–42
    [Google Scholar]
  21. 21.
    Cozzi E, White DJ. 1995. The generation of transgenic pigs as potential organ donors for humans. Nat. Med. 1:964–66
    [Google Scholar]
  22. 22.
    Chen RH, Naficy S, Logan JS, Diamond LE, Adams DH. 1999. Hearts from transgenic pigs constructed with CD59/DAF genomic clones demonstrate improved survival in primates. Xenotransplantation 6:194–200
    [Google Scholar]
  23. 23.
    Shim J, Ko N, Kim H-J, Lee Y, Lee J-W et al. 2021. Human immune reactivity of GGTA1/CMAH/A3GALT2 triple knockout Yucatan miniature pigs. Transgenic Res. 30:619–34
    [Google Scholar]
  24. 24.
    Tena A, Kurtz J, Leonard DA, Dobrinsky JR, Terlouw SL et al. 2014. Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. Am. J. Transplant. 14:2713–22
    [Google Scholar]
  25. 25.
    Yan J-J, Koo TY, Lee H-S, Lee W-B, Kang B et al. 2018. Role of human CD200 overexpression in pig-to-human xenogeneic immune response compared with human CD47 overexpression. Transplantation 102:406–16
    [Google Scholar]
  26. 26.
    Weiss EH, Lilienfeld BG, Müller S, Müller E, Herbach N et al. 2009. HLA-E/human β2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation 87:35–43
    [Google Scholar]
  27. 27.
    Rao JS, Hosny N, Kumbha R, Naqvi RA, Singh A et al. 2021. HLA-G1+ expression in GGTA1KO pigs suppresses human and monkey anti-pig T, B and NK cell responses. Front. Immunol. 12:730545
    [Google Scholar]
  28. 28.
    Wang HT, Maeda A, Sakai R, Lo PC, Takakura C et al. 2018. Human CD31 on porcine cells suppress xenogeneic neutrophil-mediated cytotoxicity via the inhibition of NETosis. Xenotransplantation 25:e12396
    [Google Scholar]
  29. 29.
    Kemter E, Lieke T, Kessler B, Kurome M, Wuensch A et al. 2012. Human TNF-related apoptosis-inducing ligand-expressing dendritic cells from transgenic pigs attenuate human xenogeneic T cell responses. Xenotransplantation 19:40–51
    [Google Scholar]
  30. 30.
    Hara H, Witt W, Crossley T, Long C, Isse K et al. 2013. Human dominant-negative class II transactivator transgenic pigs–effect on the human anti-pig T-cell immune response and immune status. Immunology 140:39–46
    [Google Scholar]
  31. 31.
    Fu R, Fang M, Xu K, Ren J, Zou J et al. 2020. Generation of GGTA1−/−β2M−/−CIITA−/− pigs using CRISPR/Cas9 technology to alleviate xenogeneic immune reactions. Transplantation 104:1566–73
    [Google Scholar]
  32. 32.
    Bähr A, Käser T, Kemter E, Gerner W, Kurome M et al. 2016. Ubiquitous LEA29Y expression blocks T cell co-stimulation but permits sexual reproduction in genetically modified pigs. PLOS ONE 11:e0155676
    [Google Scholar]
  33. 33.
    Buermann A, Petkov S, Petersen B, Hein R, Lucas-Hahn A et al. 2018. Pigs expressing the human inhibitory ligand PD-L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties. Xenotransplantation 25:e12387
    [Google Scholar]
  34. 34.
    Mohiuddin MM, Singh AK, Corcoran PC, Thomas ML III, Clark T et al. 2016. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat. Commun. 7:11138
    [Google Scholar]
  35. 35.
    Chan JL, Singh AK, Corcoran PC, Thomas ML, Lewis BG et al. 2017. Encouraging experience using multi-transgenic xenografts in a pig-to-baboon cardiac xenotransplantation model. Xenotransplantation 24:e12330
    [Google Scholar]
  36. 36.
    Wheeler DG, Joseph ME, Mahamud SD, Aurand WL, Mohler PJ et al. 2012. Transgenic swine: expression of human CD39 protects against myocardial injury. J. Mol. Cell. Cardiol. 52:958–61
    [Google Scholar]
  37. 37.
    Connolly MR, Kuravi K, Burdorf L, Sorrells L, Morrill B et al. 2021. Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models. Xenotransplantation 28:e12712
    [Google Scholar]
  38. 38.
    Paris LL, Chihara RK, Reyes LM, Sidner RA, Estrada JL et al. 2011. ASGR1 expressed by porcine enriched liver sinusoidal endothelial cells mediates human platelet phagocytosis in vitro. Xenotransplantation 18:245–51
    [Google Scholar]
  39. 39.
    Ahrens HE, Petersen B, Ramackers W, Petkov S, Herrmann D et al. 2015. Kidneys from α1, 3-galactosyltransferase knockout/human heme oxygenase-1/human A20 transgenic pigs are protected from rejection during ex vivo perfusion with human blood. Transplant. Direct 1:1–8
    [Google Scholar]
  40. 40.
    Kim GA, Lee EM, Jin J-X, Lee S, Taweechaipaisankul A et al. 2017. Generation of CMAHKO/GTKO/shTNFRI-Fc/HO-1 quadruple gene modified pigs. Transgenic Res. 26:435–45
    [Google Scholar]
  41. 41.
    Arabi TZ, Sabbah BN, Lerman A, Zhu X-Y, Lerman LO. 2023. Xenotransplantation: current challenges and emerging solutions. Cell Transplant. 32:09636897221148771
    [Google Scholar]
  42. 42.
    Ladowski JM, Hara H, Cooper DK. 2021. The role of SLAs in xenotransplantation. Transplantation 105:300–7
    [Google Scholar]
  43. 43.
    Mok D, Black M, Gupta N, Arefanian H, Tredget E, Rayat GR. 2019. Early immune mechanisms of neonatal porcine islet xenograft rejection. Xenotransplantation 26:e12546
    [Google Scholar]
  44. 44.
    Fox A, Mountford J, Braakhuis A, Harrison LC. 2001. Innate and adaptive immune responses to nonvascular xenografts: evidence that macrophages are direct effectors of xenograft rejection. J. Immunol. 166:2133–40
    [Google Scholar]
  45. 45.
    Xu XC, Goodman J, Sasaki H, Lowell J, Mohanakumar T. 2002. Activation of natural killer cells and macrophages by porcine endothelial cells augments specific T-cell xenoresponse. Am. J. Transplant. 2:314–22
    [Google Scholar]
  46. 46.
    Cadili A, Kneteman N. 2008. The role of macrophages in xenograft rejection. Transplant. Proc. 40:3289–93
    [Google Scholar]
  47. 47.
    El-Ouaghlidi A, Jahr H, Pfeiffer G, Hering BJ, Brandhorst D et al. 1999. Cytokine mRNA expression in peripheral blood cells of immunosuppressed human islet transplant recipients. J. Mol. Med. 77:115–17
    [Google Scholar]
  48. 48.
    Oldenborg P-A, Zheleznyak A, Fang Y-F, Lagenaur CF, Gresham HD, Lindberg FP. 2000. Role of CD47 as a marker of self on red blood cells. Science 288:2051–54
    [Google Scholar]
  49. 49.
    Cooper DK, Hara H, Iwase H, Yamamoto T, Li Q et al. 2019. Justification of specific genetic modifications in pigs for clinical organ xenotransplantation. Xenotransplantation 26:e12516
    [Google Scholar]
  50. 50.
    Cooper DK, Ezzelarab MB, Hara H, Iwase H, Lee W et al. 2016. The pathobiology of pig-to-primate xenotransplantation: a historical review. Xenotransplantation 23:83–105
    [Google Scholar]
  51. 51.
    Zeng G, Jiang Y, Feng C, Shi N, Long C et al. 2016. Generation and expression analysis of human (Homo sapiens) CD47 transgenic Bama miniature pig (Sus scrofa). J. Agric. Biotechnol. 24:1251–58
    [Google Scholar]
  52. 52.
    Rijkers ES, de Ruiter T, Baridi A, Veninga H, Hoek RM, Meyaard L. 2008. The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. Mol. Immunol. 45:1126–35
    [Google Scholar]
  53. 53.
    Sakai R, Maeda A, Choi T-V, Lo P-C, Jiaravuthisan P et al. 2018. Human CD200 suppresses macrophage-mediated xenogeneic cytotoxicity and phagocytosis. Surg. Today 48:119–26
    [Google Scholar]
  54. 54.
    Maeda A, Kogata S, Toyama C, Lo P-C, Okamatsu C et al. 2022. The innate cellular immune response in xenotransplantation. Front. Immunol. 13:858604
    [Google Scholar]
  55. 55.
    Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. 2013. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol. 31:227–58
    [Google Scholar]
  56. 56.
    Zhuang B, Shang J, Yao Y. 2021. HLA-G: an important mediator of maternal-fetal immune-tolerance. Front. Immunol. 12:744324
    [Google Scholar]
  57. 57.
    Forte P, Lilienfeld BG, Baumann BC, Seebach D Jr. 2005. Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D. J. Immunol. 175:5463–70
    [Google Scholar]
  58. 58.
    Lilienfeld BG, Garcia-Borges C, Crew MD, Seebach JD. 2006. Porcine UL16-binding protein 1 expressed on the surface of endothelial cells triggers human NK cytotoxicity through NKG2D. J. Immunol. 177:2146–52
    [Google Scholar]
  59. 59.
    Lei T, Chen L, Wang K, Du S, Gonelle-Gispert C et al. 2022. Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: the first clinical steps. Front. Immunol. 13:1031185
    [Google Scholar]
  60. 60.
    Vorobjeva N, Chernyak B. 2020. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry 85:1178–90
    [Google Scholar]
  61. 61.
    Kimura K, Shirabe K, Yoshizumi T, Takeishi K, Itoh S et al. 2016. Ischemia-reperfusion injury in fatty liver is mediated by activated NADPH oxidase 2 in rats. Transplantation 100:791–800
    [Google Scholar]
  62. 62.
    Sil P, Wicklum H, Surell C, Rada B. 2017. Macrophage-derived IL-1β enhances monosodium urate crystal-triggered NET formation. Inflamm. Res. 66:227–37
    [Google Scholar]
  63. 63.
    Dong X, Swaminathan S, Bachman L-A, Croatt A-J, Nath K-A, Griffin M-D. 2007. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia–reperfusion injury. Kidney Int. 71:619–28
    [Google Scholar]
  64. 64.
    Lin J, Wang H, Liu C, Cheng A, Deng Q et al. 2021. Dendritic cells: versatile players in renal transplantation. Front. Immunol. 12:1669
    [Google Scholar]
  65. 65.
    Scalea J, Hanecamp I, Robson SC, Yamada K. 2012. T-cell-mediated immunological barriers to xenotransplantation. Xenotransplantation 19:23–30
    [Google Scholar]
  66. 66.
    Hu M, Hawthorne WJ, Yi S, O'Connell PJ. 2022. Cellular immune responses in islet xenograft rejection. Front. Immunol. 13:893985
    [Google Scholar]
  67. 67.
    Griesemer A, Yamada K, Sykes M. 2014. Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol. Rev. 258:241–58
    [Google Scholar]
  68. 68.
    Sake HJ, Frenzel A, Lucas-Hahn A, Nowak-Imialek M, Hassel P et al. 2019. Possible detrimental effects of beta-2-microglobulin knockout in pigs. Xenotransplantation 26:e12525
    [Google Scholar]
  69. 69.
    Hein R, Sake HJ, Pokoyski C, Hundrieser J, Brinkmann A et al. 2020. Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—effects on immune status and susceptibility to human immune responses. Am. J. Transplant. 20:988–98
    [Google Scholar]
  70. 70.
    Li XC, Rothstein DM, Sayegh MH. 2009. Costimulatory pathways in transplantation: challenges and new developments. Immunol. Rev. 229:271–93
    [Google Scholar]
  71. 71.
    Vabres B, Le Bas-Bernardet S, Riochet D, Cherel Y, Minault D et al. 2014. hCTLA 4-Ig transgene expression in keratocytes modulates rejection of corneal xenografts in a pig to non-human primate anterior lamellar keratoplasty model. Xenotransplantation 21:431–43
    [Google Scholar]
  72. 72.
    Mohiuddin MM, Singh AK, Corcoran PC, Hoyt RF, Thomas ML III et al. 2014. Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon model. Xenotransplantation 21:35–45
    [Google Scholar]
  73. 73.
    Mackman N. 2008. Triggers, targets and treatments for thrombosis. Nature 451:914–18
    [Google Scholar]
  74. 74.
    Cowan PJ, Robson SC, d'Apice AJF. 2011. Controlling coagulation dysregulation in xenotransplantation. Curr. Opin. Organ Transplant. 16:214–21
    [Google Scholar]
  75. 75.
    Cross-Najafi AA, Lopez K, Isidan A, Park Y, Zhang W et al. 2022. Current barriers to clinical liver xenotransplantation. Front. Immunol. 13:827535
    [Google Scholar]
  76. 76.
    Zhang X, Wang Q, Zhao J, Li X, Peng W et al. 2021. The resurgent landscape of xenotransplantation of pig organs in nonhuman primates. Sci. China Life Sci. 64:697–708
    [Google Scholar]
  77. 77.
    Cowan PJ. 2007. Coagulation and the xenograft endothelium. Xenotransplantation 14:7–12
    [Google Scholar]
  78. 78.
    Kim SC, Mathews DV, Breeden CP, Higginbotham LB, Ladowski J et al. 2019. Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion. Am. J. Transplant. 19:2174–85
    [Google Scholar]
  79. 79.
    Mohiuddin MM, Singh AK, Corcoran PC, Hoyt RF, Thomas ML III et al. 2014. Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation. J. Thorac. Cardiovasc. Surg. 148:1106–14
    [Google Scholar]
  80. 80.
    Li J, Hara H, Wang Y, Esmon C, Cooper DK, Iwase H. 2019. Evidence for the important role of inflammation in xenotransplantation. J. Inflamm. 16:10
    [Google Scholar]
  81. 81.
    Liu Y, Niu Y, Ma X, Xiang Y, Wu D et al. 2023. Porcine endogenous retrovirus: classification, molecular structure, regulation, function, and potential risk in xenotransplantation. Funct. Integr. Genom. 23:60
    [Google Scholar]
  82. 82.
    Denner J. 2022. Virus safety of xenotransplantation. Viruses 14:1926
    [Google Scholar]
  83. 83.
    Noordergraaf J, Schucker A, Martin M, Schuurman H-J, Ordway B et al. 2018. Pathogen elimination and prevention within a regulated, Designated Pathogen Free, closed pig herd for long-term breeding and production of xenotransplantation materials. Xenotransplantation 25:e12428
    [Google Scholar]
  84. 84.
    Denner J. 2016. How active are porcine endogenous retroviruses (PERVs)?. Viruses 8:215
    [Google Scholar]
  85. 85.
    Denner J. 2021. The origin of porcine endogenous retroviruses (PERVs). Arch. Virol. 166:1007–13
    [Google Scholar]
  86. 86.
    Güell M, Niu D, Kan Y, George H, Wang T et al. 2017. PERV inactivation is necessary to guarantee absence of pig-to-patient PERVs transmission in xenotransplantation. Xenotransplantation 24:e12366
    [Google Scholar]
  87. 87.
    Mehta SA, Saharia KK, Nellore A, Blumberg EA, Fishman JA. 2023. Infection and clinical xenotransplantation: Guidance from the Infectious Disease Community of Practice of the American Society of Transplantation. Am. J. Transplant. 23:309–15
    [Google Scholar]
  88. 88.
    Gałka S, Nowak E, Bednarek I. 2022. Selective human cells in vitro transduction with porcine endogenous retrovirus (PERV). Acta Virol. 66:110–26
    [Google Scholar]
  89. 89.
    Lu T-f, Sun B, Yu T-y, Wu Y-j, Zhou J, Wu S-g. 2022. Porcine endogenous retroviruses: quantification of the viral copy number for the four miniature pig breeds in China. Front. Microbiol. 13:840347
    [Google Scholar]
  90. 90.
    Niu D, Wei H-J, Lin L, George H, Wang T et al. 2017. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science 357:1303–7
    [Google Scholar]
  91. 91.
    Yue Y, Xu W, Kan Y, Zhao H-Y, Zhou Y et al. 2021. Extensive germline genome engineering in pigs. Nat. Biomed. Eng. 5:134–43
    [Google Scholar]
  92. 92.
    Zheng S, Zhong H, Zhou X, Chen M, Li W et al. 2022. Efficient and safe editing of porcine endogenous retrovirus genomes by multiple-site base-editing editor. Cells 11:3975
    [Google Scholar]
  93. 93.
    Griffith BP, Goerlich CE, Singh AK, Rothblatt M, Lau CL et al. 2022. Genetically modified porcine-to-human cardiac xenotransplantation. N. Engl. J. Med. 387:35–44
    [Google Scholar]
  94. 94.
    Shu S, Ren J, Song J. 2022. Cardiac xenotransplantation: a promising way to treat advanced heart failure. Heart Fail. Rev. 27:71–91
    [Google Scholar]
  95. 95.
    Längin M, Mayr T, Reichart B, Michel S, Buchholz S et al. 2018. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564:430–33
    [Google Scholar]
  96. 96.
    Hinrichs A, Kessler B, Kurome M, Blutke A, Kemter E et al. 2018. Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver. Mol. Metab. 11:113–28
    [Google Scholar]
  97. 97.
    Goerlich CE, Griffith B, Hanna P, Hong SN, Ayares D et al. 2021. The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors. J. Thorac. Cardiovasc. Surg. 165:e69–e81
    [Google Scholar]
  98. 98.
    Nilsson J, Jernryd V, Qin G, Paskevicius A, Metzsch C et al. 2020. A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation. Nat. Commun. 11:2976
    [Google Scholar]
  99. 99.
    Längin M, Reichart B, Steen S, Sjöberg T, Paskevicius A et al. 2021. Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation. Xenotransplantation 28:e12636
    [Google Scholar]
  100. 100.
    Moazami N, Stern JM, Khalil K, Kim JI, Narula N et al. 2023. Pig-to-human heart xenotransplantation in two recently deceased human recipients. Nat. Med. 29:1989–97
    [Google Scholar]
  101. 101.
    Walker JT, Saunders DC, Brissova M, Powers AC. 2021. The human islet: mini-organ with mega-impact. Endocr. Rev. 42:605–57
    [Google Scholar]
  102. 102.
    Hammerman MR. 2013. Xenotransplantation of embryonic pig pancreas for treatment of diabetes mellitus in non-human primates. J. Biomed. Sci. Eng. 6:6–11
    [Google Scholar]
  103. 103.
    Naqvi RA, Naqvi AR, Singh A, Priyadarshini M, Balamurugan AN, Layden BT. 2022. The future treatment for type 1 diabetes: Pig islet-or stem cell-derived β cells?. Front. Endocrinol. 13:1001041
    [Google Scholar]
  104. 104.
    Rayat G, Rajotte R, Hering B, Binette T, Korbutt G. 2003. In vitro and in vivo expression of Galα-(1,3)Gal on porcine islet cells is age dependent. J. Endocrinol. 177:127–35
    [Google Scholar]
  105. 105.
    Citro A, Neroni A, Pignatelli C, Campo F, Policardi M et al. 2023. Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes. Nat. Commun. 14:878
    [Google Scholar]
  106. 106.
    Honarpisheh M, Lei Y, Zhang Y, Pehl M, Kemter E et al. 2022. Formation of re-aggregated neonatal porcine islet clusters improves in vitro function and transplantation outcome. Transpl. Int. 35:10697
    [Google Scholar]
  107. 107.
    Zhang Y, Lei Y, Honarpisheh M, Kemter E, Wolf E, Seissler J. 2021. Butyrate and class I histone deacetylase inhibitors promote differentiation of neonatal porcine islet cells into beta cells. Cells 10:3249
    [Google Scholar]
  108. 108.
    Kemter E, Wolf E. 2018. Recent progress in porcine islet isolation, culture and engraftment strategies for xenotransplantation. Curr. Opin. Organ. Transplant. 23:633–41
    [Google Scholar]
  109. 109.
    Kanak MA, Saravanan PB, Levy MF. 2019. Inflammatory response and its impact on outcome of islet transplantation. CellR4 7:e2739
    [Google Scholar]
  110. 110.
    Shin JS, Min BH, Kim JM, Kim JS, Yoon IH et al. 2016. Failure of transplantation tolerance induction by autologous regulatory T cells in the pig-to-non-human primate islet xenotransplantation model. Xenotransplantation 23:300–9
    [Google Scholar]
  111. 111.
    van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C et al. 2009. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am. J. Transplant. 9:2716–26
    [Google Scholar]
  112. 112.
    Thompson P, Badell I, Lowe M, Cano J, Song M et al. 2011. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am. J. Transplant. 11:2593–602
    [Google Scholar]
  113. 113.
    Hawthorne W, Salvaris E, Phillips P, Hawkes J, Liuwantara D et al. 2014. Control of IBMIR in neonatal porcine islet xenotransplantation in baboons. Am. J. Transplant. 14:1300–9
    [Google Scholar]
  114. 114.
    Bottino R, Wijkstrom M, van Der Windt D, Hara H, Ezzelarab M et al. 2014. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am. J. Transplant. 14:2275–87
    [Google Scholar]
  115. 115.
    Samy KP, Gao Q, Davis RP, Song M, Fitch ZW et al. 2019. The role of human CD46 in early xenoislet engraftment in a dual transplant model. Xenotransplantation 26:e12540
    [Google Scholar]
  116. 116.
    Song M, Fitch ZW, Samy KP, Martin BM, Gao Q et al. 2021. Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation. Xenotransplantation 28:e12680
    [Google Scholar]
  117. 117.
    Hawthorne WJ, Salvaris EJ, Chew YV, Burns H, Hawkes J et al. 2022. Xenotransplantation of genetically modified neonatal pig islets cures diabetes in baboons. Front. Immunol. 13:898948
    [Google Scholar]
  118. 118.
    Buerck LW-v, Schuster M, Oduncu FS, Baehr A, Mayr T et al. 2017. LEA29Y expression in transgenic neonatal porcine islet-like cluster promotes long-lasting xenograft survival in humanized mice without immunosuppressive therapy. Sci. Rep. 7:3572
    [Google Scholar]
  119. 119.
    Klymiuk N, van Buerck L, Bähr A, Offers M, Kessler B et al. 2012. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes 61:1527–32
    [Google Scholar]
  120. 120.
    Zhang Q, Gonelle-Gispert C, Li Y, Geng Z, Gerber S et al. 2022. Islet encapsulation: new developments for the treatment of type 1 diabetes. Front. Immunol. 13:869984
    [Google Scholar]
  121. 121.
    Matsumoto S, Abalovich A, Wechsler C, Wynyard S, Elliott RB. 2016. Clinical benefit of islet xenotransplantation for the treatment of type 1 diabetes. EBioMedicine 12:255–62
    [Google Scholar]
  122. 122.
    Morozov VA, Wynyard S, Matsumoto S, Abalovich A, Denner J, Elliott R. 2017. No PERV transmission during a clinical trial of pig islet cell transplantation. Virus Res. 227:34–40
    [Google Scholar]
  123. 123.
    Matsumoto S, Tan P, Baker J, Durbin K, Tomiya M et al. 2014. Clinical porcine islet xenotransplantation under comprehensive regulation. Transplant. Proc. 46:1992–95
    [Google Scholar]
  124. 124.
    Ren G, Rezaee M, Razavi M, Taysir A, Wang J, Thakor AS. 2019. Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties. Cell Tissue Res. 376:353–64
    [Google Scholar]
  125. 125.
    Razavi M, Ren T, Zheng F, Telichko A, Wang J et al. 2020. Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound. Stem Cell Res. Ther. 11:405
    [Google Scholar]
  126. 126.
    Princeteau M. 1905. Greffe renale. J. Med. Bord. 26:549
    [Google Scholar]
  127. 127.
    Rodger D, Cooper DK. 2022. Kidney xenotransplantation: Future clinical reality or science fiction?. Nurs. Health Sci. 25:161–70
    [Google Scholar]
  128. 128.
    Iwase H, Hara H, Ezzelarab M, Li T, Zhang Z et al. 2017. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation 24:e12293
    [Google Scholar]
  129. 129.
    Iwase H, Liu H, Wijkstrom M, Zhou H, Singh J et al. 2015. Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date. Xenotransplantation 22:302–9
    [Google Scholar]
  130. 130.
    Adams AB, Kim SC, Martens GR, Ladowski JM, Estrada JL et al. 2018. Xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival. Ann. Surg. 268:564–73
    [Google Scholar]
  131. 131.
    Ma D, Hirose T, Lassiter G, Sasaki H, Rosales I et al. 2022. Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques. Am. J. Transplant. 22:46–57
    [Google Scholar]
  132. 132.
    Firl DJ, Lassiter G, Hirose T, Policastro R, D'Attilio A et al. 2023. Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation. Nat. Commun. 14:3022
    [Google Scholar]
  133. 133.
    Anand RP, Layer JV, Heja D, Hirose T, Lassiter G et al. 2023. Design and testing of a humanized porcine donor for xenotransplantation. Nature 622:393–401
    [Google Scholar]
  134. 134.
    Montgomery RA, Stern JM, Lonze BE, Tatapudi VS, Mangiola M et al. 2022. Results of two cases of pig-to-human kidney xenotransplantation. N. Engl. J. Med. 386:1889–98
    [Google Scholar]
  135. 135.
    Porrett PM, Orandi BJ, Kumar V, Houp J, Anderson D et al. 2022. First clinical-grade porcine kidney xenotransplant using a human decedent model. Am. J. Transplant. 22:1037–53
    [Google Scholar]
  136. 136.
    Montgomery R. 2023. Pig kidney xenotransplantation performing optimally after 32 days in human body. Press Rel., Aug. 16 NYU Langone Health NY: https://nyulangone.org/news/pig-kidney-xenotransplantation-performing-optimally-after-32-days-human-body
  137. 137.
    Burlak C, Paris LL, Chihara RK, Sidner RA, Reyes LM et al. 2010. The fate of human platelets perfused through the pig liver: implications for xenotransplantation. Xenotransplantation 17:350–61
    [Google Scholar]
  138. 138.
    Paris LL, Estrada JL, Li P, Blankenship RL, Sidner RA et al. 2015. Reduced human platelet uptake by pig livers deficient in the asialoglycoprotein receptor 1 protein. Xenotransplantation 22:203–10
    [Google Scholar]
  139. 139.
    Cimeno A, Kuravi K, Sorrells L, Dandro A, Sendil S et al. 2022. hEPCR.hTBM.hCD47.hHO-1 with donor clodronate and DDAVP treatment improves perfusion and function of GalTKO.hCD46 porcine livers perfused with human blood. Xenotransplantation 29:e12731
    [Google Scholar]
  140. 140.
    Ekser B, Long C, Echeverri G, Hara H, Ezzelarab M et al. 2010. Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants: clinical relevance. Am. J. Transplant. 10:273–85
    [Google Scholar]
  141. 141.
    Ekser B, Klein E, He J, Stolz DB, Echeverri GJ et al. 2012. Genetically-engineered pig-to-baboon liver xenotransplantation: histopathology of xenografts and native organs. PLOS ONE 7:e29720
    [Google Scholar]
  142. 142.
    Shah JA, Navarro-Alvarez N, DeFazio M, Rosales IA, Elias N et al. 2016. A bridge to somewhere: 25-day survival after pig-to-baboon liver xenotransplantation. Ann. Surg. 263:1069–71
    [Google Scholar]
  143. 143.
    Shah J, Patel M, Elias N, Navarro-Alvarez N, Rosales I et al. 2017. Prolonged survival following pig-to-primate liver xenotransplantation utilizing exogenous coagulation factors and costimulation blockade. Am. J. Transplant. 17:2178–85
    [Google Scholar]
  144. 144.
    Li X, Wang Y, Yang H, Dai Y. 2022. Liver and hepatocyte transplantation: What can pigs contribute?. Front. Immunol. 12:802692
    [Google Scholar]
  145. 145.
    Chaban R, Cooper DK, Pierson RN III. 2022. Pig heart and lung xenotransplantation: present status. J. Heart Lung Transplant. 41:1014–22
    [Google Scholar]
  146. 146.
    Nguyen B-NH, Azimzadeh AM, Zhang T, Wu G, Shuurman H-J et al. 2007. Life-supporting function of genetically modified swine lungs in baboons. J. Thorac. Cardiovasc. Surg. 133:1354–63
    [Google Scholar]
  147. 147.
    Watanabe H, Sahara H, Nomura S, Tanabe T, Ekanayake-Alper DK et al. 2018. GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels. Xenotransplantation 25:e12391
    [Google Scholar]
  148. 148.
    Burdorf L, Laird C, Sendil S, O'Neill N, Zhang T et al. 2019. 31 day xeno lung recipient survival-progress towards the clinic. J. Heart Lung Transplant. 38:S39
    [Google Scholar]
  149. 149.
    GBD 2019 Blind. Vis. Impair. Collab., Vis. Loss Exp. Group Global Burd. Dis. Stud 2021. Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study. Lancet Global Health 9:e130–e43
    [Google Scholar]
  150. 150.
    Choi HJ, Yoon CH, Kim MK. 2019. Updates on corneal xenotransplantation. Curr. Ophthalmol. Rep. 7:30–36
    [Google Scholar]
  151. 151.
    Yoon CH, Choi HJ, Kim MK. 2021. Corneal xenotransplantation: Where are we standing?. Prog. Retin. Eye Res. 80:100876
    [Google Scholar]
  152. 152.
    Lee HI, Kim MK, Oh JY, Ko JH, Lee HJ et al. 2007. Galα(1–3)Gal expression of the cornea in vitro, in vivo and in xenotransplantation. Xenotransplantation 14:612–18
    [Google Scholar]
  153. 153.
    Choi H, Lee J, Kim D, Kim MK, Lee H et al. 2015. Blockade of CD40–CD154 costimulatory pathway promotes long-term survival of full-thickness porcine corneal grafts in nonhuman primates: clinically applicable xenocorneal transplantation. Am. J. Transplant. 15:628–41
    [Google Scholar]
  154. 154.
    Yoon CH, Choi SH, Choi HJ, Lee HJ, Kang HJ et al. 2020. Long-term survival of full-thickness corneal xenografts from α1,3-galactosyltransferase gene-knockout miniature pigs in non-human primates. Xenotransplantation 27:e12559
    [Google Scholar]
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