Xenotransplantation最新文献

{"title":"Integrated Multi-Omics Analysis of Coagulation Dysregulation and Immune Pathway Alterations in 10-Gene Pig-to-Monkey Liver Xenotransplantation: A Case Report.","authors":"Wei Zhang, Rongrong Wang, Xuan Zhang, Zhiwei Li, Yinan Shen, Min Xu, Xin Duan, Ying Chen, Jie Xiang, Xiaoyuan Zhang, Yingjiqiong Liang, Huanglei Tang, Jinyan Huang, Shunliang Gao, Kaixiang Xu, Xueli Bai, Hongjiang Wei, Tingbo Liang","doi":"10.1111/xen.70132","DOIUrl":"https://doi.org/10.1111/xen.70132","url":null,"abstract":"<p><p>Liver xenotransplantation has the potential to address the global shortage of donor organs; however, coagulation dysregulation remains a predominant barrier to long-term liver xenograft survival. In this study, orthotopic liver xenotransplantation was performed using a 10-gene-edited (GTKO/CMAHKO/β4GalNT2KO/hCD46/hCD55/hCD59/hTBM/hCD39/hEPCR/hCD47) porcine donor liver transplanted into a nonhuman primate recipient. Independent of graft function, which remained stable, an unexpected interruption of the oxygen supply on POD 3 triggered a terminal event, leading to death on POD 4. Despite technical success, rapid consumptive coagulopathy developed within 24 h, characterized by severe thrombocytopenia, fibrinogen depletion, and prolongation of coagulation times. Declining plasma von Willebrand factor activity (vWF) and reduced graft vWF expression accompanied these changes. Integrated longitudinal hematologic monitoring, histopathology, transcriptomics, and proteomics were used to define early graft injury. Histological analysis demonstrated microvascular injury with macrophage and B cell infiltration and immunoglobulin deposition, without T cell involvement. Molecular profiling revealed a dominant recipient innate immune response enriched for macrophage-mediated phagocytosis, adhesion, and proteasome pathways, alongside activation of complement and coagulation cascades. Concurrently, the donor graft showed downregulation of key metabolic enzymes, indicating early metabolic stress. These findings indicate that macrophage-driven innate immunity and systemic coagulation exhaustion represent principal early challenges in liver xenotransplantation, highlighting the complement-coagulation axis and macrophage activation as critical therapeutic targets for improving xenograft outcomes. However, given the intense induction immunosuppression and early severe systemic inflammation, these multi-omics findings reflect a complex interplay of graft injury and pharmacological intervention, requiring cautious interpretation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70132"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is There an Ethical Dilemma in Xenotransplantation?","authors":"Joachim Denner","doi":"10.1111/xen.70135","DOIUrl":"10.1111/xen.70135","url":null,"abstract":"<p><p>As clinical trials in xenotransplantation commence, the question of whether participants may withdraw from research is being intensely debated. Some authors argue that xenotransplant recipients should be subject to lifelong monitoring because of the potential risk of zoonotic or xenozoonotic infections affecting third parties. Others maintain that the right to withdraw from research participation is a fundamental principle of medical ethics that must not be compromised. To clarify this tension, historical precedents have been examined, and the applicability of so-called Ulysses contracts to xenotransplantation has been critically assessed. The practical answer is more straightforward than the theoretical debate suggests: xenotransplant recipients, like allotransplant recipients, require continuous medical supervision. Lifelong immunosuppression and regular follow-up are essential to preserve transplant function and, ultimately, the patient's life.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70135"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological Approaches to Improve the Robustness of Bibliometric Studies in Xenotransplantation.","authors":"Shangxuan Li, Dongsheng He, Xianzhi Wang, Guanzheng Cui, Ziqiang Dai, Zhipeng Ren, Dianyuan Li","doi":"10.1111/xen.70141","DOIUrl":"https://doi.org/10.1111/xen.70141","url":null,"abstract":"","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70141"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of Cloned Sheep Lacking Galactose-α1,3-Galactose and N-Glycolylneuraminic Acid Antigens.","authors":"Sarah J Appleby, Lisanne M Fermin, Zachariah L McLean, Stephanie Delaney, Stefan Wagner, Cecilia Di Genova, Jingwei Wei, Fanli Meng, David N Wells, Björn Oback","doi":"10.1111/xen.70134","DOIUrl":"https://doi.org/10.1111/xen.70134","url":null,"abstract":"<p><p>Livestock have long been regarded as a potential source of donor organs to alleviate the global organ shortage for transplantation. Sheep have a similar anatomy to humans, providing the standard model for demonstrating biocompatibility and performance of biological heart valves to obtain regulatory approval for their use in transplantation. Like most mammals, sheep cells contain two well-characterized carbohydrate epitopes, galactose-α1,3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc), which are absent in humans. Formation of these xenoantigens is catalyzed by two enzymes, namely α1,3 galactosyltransferase (GGTA1) and CMP-Neu5Gc hydroxylase (CMAH), respectively. Towards generating new sheep models, we used Cas9-mediated genome editing in both male and female ovine fetal fibroblasts to knockout (KO) both alleles of CMAH and GGTA1. Selected double KO (DKO) fibroblast strains were used for somatic cell transfer cloning to produce blastocysts that were transferred into gestational surrogate ewes. Following the transfer of 128 male and 40 female cloned blastocysts, six male and eight female lambs were born; however, none of the males survived. Molecular analyses of cells from the five surviving ewes confirmed their compound heterozygous state, resulting in a functional DKO phenotype and subsequent immune rejection of embryonic tissues during natural breeding with wild-type rams. This new DKO sheep model better mimics the human immune status, offering greater physiological relevance for preclinical testing of biological heart valves, alleviation of red meat allergy syndrome due to the presence of dietary xenoantigens, and a widely culturally acceptable alternative source of certain donor organs.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70134"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xenoperfusion-The Transformative Role of Machine Perfusion in Xenotransplantation.","authors":"Florian Huwyler, Simon Stoerzer, Pierre-Alain Clavien, Mark W Tibbitt","doi":"10.1111/xen.70131","DOIUrl":"10.1111/xen.70131","url":null,"abstract":"<p><p>Recent advances in xenotransplantation have gained substantial public and clinical attention as genetically modified porcine organs are now being transplanted into living human recipients. While only case reports have been published to date, the first clinical trials for kidney xenotransplantation are now ongoing. This transition to clinical practice presents multiple implementation challenges for establishing scalable transplant programs while ensuring patient safety. Machine perfusion is expected to play a critical role in addressing these challenges by serving as a central platform for organ preservation, assessment, transport, and therapeutic intervention. Given the limited number of designated pathogen-free (DPF) breeding facilities, regional and international organ transport depends on robust preservation strategies during transit. Additionally, perfusion devices enable essential pre-transplant screening for zoonotic pathogens, a crucial safety measure unique to xenotransplantation. Further, given recent developments that allow for multi-day perfusion of grafts, wild-type grafts could potentially be genetically modified while being perfused ex situ. Beyond these perfusion modalities of isolated whole organs, machine perfusion offers a new therapeutic approach for patients with acute liver failure. Here, cross-circulation between a perfused genetically modified porcine organ and the patient can provide temporary liver replacement therapy. This mini-review summarizes the transformative potential of machine perfusion technology in clinical xenotransplantation with a focus on livers.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70131"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pig Kidney Xenotransplantation Rewrites the Rules of Renal Graft Rejection.","authors":"Wen-Bin Liu, Hong-Liang Rui, Bao-Li Liu","doi":"10.1111/xen.70130","DOIUrl":"https://doi.org/10.1111/xen.70130","url":null,"abstract":"<p><p>The recent milestone publication by Schmauch et al. in Nature (650 (2026): 205-217) describes a 61-day longitudinal multi-omics analysis of a gene-edited pig-to-human kidney xenotransplant in a brain-dead decedent. This study provides an unprecedented high-resolution map of the xenogeneic immune response. In this commentary, we move beyond summary to interpret these findings through a clinical transplant lens, contrasting xenograft rejection with established experience in human renal allografts. This comparison highlights practice-relevant differences in immune hierarchy, rejection chronology, and the dominant contribution of innate and humoral immunity. Recognizing these differences-moving from the \"civil war\" of allotransplantation to the \"interspecies conflict\" of xenotransplantation-will be essential for designing first-in-human trials, tailoring immunosuppressive regimens, and building rational monitoring strategies as the field advances toward living recipients.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 2","pages":"e70130"},"PeriodicalIF":4.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Public Awareness and Acceptance of Xenotransplantation: A National Survey in China.","authors":"Hongmin Kuang, Xin Hong, Jingjun Zhao, Jianlin Wang, Kefeng Dou, Xuan Zhang","doi":"10.1111/xen.70117","DOIUrl":"https://doi.org/10.1111/xen.70117","url":null,"abstract":"<p><strong>Background: </strong>Xenotransplantation (XTx), as a crucial direction for addressing the shortage of allogeneic donors, has achieved significant progress and garnered widespread attention in China. However, this field still faces multiple challenges at the ethical, legal, and social levels, making it particularly critical to systematically understand public attitudes and perceptions regarding XTx. This study aims to investigate the knowledge and acceptance of the Chinese population toward XTx.</p><p><strong>Methods: </strong>A 47-item questionnaire was designed to explore the Chinese public's knowledge and acceptance of XTx. It was distributed and collected via the \"Wenjuanxing\" platform (a Chinese online survey tool), getting 2651 valid responses. Nonparametric tests and generalized linear models were performed with SPSS software to test the proposed relationships.</p><p><strong>Results: </strong>The overall public acceptance score for XTx was 98 (82, 104), indicating a moderate level of acceptance (67.59%). Among the dimensions, \"Knowledge and Attitude\" scored the highest (72.72%), while \"Risks and Concerns\" was the lowest (60.00%). Multivariable analyses identified key independent factors influencing acceptance. Males, individuals with higher education, urban residents, and those willing about uncompensated donation had significantly higher total scores. Conversely, females, individuals with religious beliefs, nonmedical professionals, and those with personal/family-related transplant experiences had significantly lower scores. Dimension-specific analyses yielded several insights. Higher income mitigated risk concerns. Additionally, healthcare professionals held more positive views on efficacy and cost than other groups.</p><p><strong>Conclusions: </strong>The Chinese public demonstrates a relatively high level of awareness and a moderately favorable acceptance of XTx. However, respondents exhibit incomplete knowledge of inherent residual risks, immune rejection, and long-term efficacy in XTx. At the same time, they hold overly optimistic expectations regarding its therapeutic outcomes and associated costs.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 2","pages":"e70117"},"PeriodicalIF":4.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renin-Angiotensin-Aldosterone System (RAAS) in Pig-to-Baboon Kidney Xenotransplantation-Relevance to Clinical Pig Kidney Xenotransplantation.","authors":"Maho Terashita, Kohei Kinoshita, Ryousuke Satou, Akemi Katsurada, Gweneth Eliza Lavalla, Akihiro Maenaka, Yuji Hidaka, Ivy A Rosales, David Ayares, Tatsuo Kawai, Luis Gabriel Navar, David K C Cooper","doi":"10.1111/xen.70129","DOIUrl":"https://doi.org/10.1111/xen.70129","url":null,"abstract":"<p><strong>Background: </strong>Pig-to-human kidney xenotransplantation offers a potential solution to the organ shortage. However, the ability of the transplanted pig kidney to regulate blood pressure and fluid balance remains uncertain. The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in these functions, but species differences may impair its effectiveness in xenotransplantation.</p><p><strong>Methods: </strong>Gene-edited pig kidneys were transplanted into six immunosuppressed baboons. Group A (n = 2) underwent bilateral native nephrectomy, while Group B (n = 4) had unilateral nephrectomy with one native kidney remaining in situ (with its ureter ligated) to avoid it contributing to salt and volume regulation. Plasma creatinine, potassium, renin, angiotensinogen, angiotensin I, and aldosterone levels were measured.</p><p><strong>Results: </strong>Group A, but not Group B, exhibited increases in plasma creatinine and potassium levels, indicating hypovolemia that could be corrected by frequent fluid administration. Pig-specific renin was undetectable at all post-transplant time points in both groups. Baboon renin concentration and activity were measurable only in Group B, indicating that the native kidney contributed to renin production. Aldosterone levels remained unchanged in both groups.</p><p><strong>Conclusions: </strong>The absence of detectable pig renin highlights a potential physiological challenge in xenotransplantation. However, the retention of a native kidney may help maintain RAAS function and mitigate fluid and electrolyte imbalances. In clinical pig-to-human kidney transplantation, both native kidneys are usually retained, thus minimizing the development of hypovolemia.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 2","pages":"e70129"},"PeriodicalIF":4.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver Xenotransplantation: Ethical and Societal Implications.","authors":"Daniel J Hurst, Christopher A Bobier, Luz A Padilla, Anthony Merlocco, Raphael P H Meier","doi":"10.1111/xen.70116","DOIUrl":"10.1111/xen.70116","url":null,"abstract":"<p><p>The shortage of transplantable livers and high waitlist mortality rates have accelerated the clinical translation of liver xenotransplantation. Recent milestones, including extracorporeal perfusion models and gene-edited pig-to-human transplants in both decedents and living patients, indicate that clinical trials may be imminent. While the ethics of solid organ xenotransplantation generally-such as animal welfare, xenozoonosis, and informed consent-have been debated, the specific implications of liver xenotransplantation remain underexplored. This article examines these unique challenges. We argue that pediatric liver xenotransplantation research might proceed simultaneously with adult research due to high waitlist mortality among infants. In adults, we analyze how liver xenotransplantation intersects with historical controversies regarding patient selection, specifically concerning alcohol-associated liver disease and hepatocellular carcinoma. We explore the ethical risks of a potential dual pathway allocation system that could bifurcate waitlists based on disease etiology, raising concerns regarding distributive justice and the stigmatization of addiction. Finally, we consider whether xenografts might serve as a trial of time for patients currently ineligible for allotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 2","pages":"e70116"},"PeriodicalIF":4.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13002998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precise Multi-Gene Editing Strategies for Xenotransplantation Donor Pigs: Overcoming Immune and Coagulation Barriers.","authors":"Qianqian Li, Jingchao Cao, Shoulong Deng, Kun Yu","doi":"10.1111/xen.70128","DOIUrl":"https://doi.org/10.1111/xen.70128","url":null,"abstract":"<p><p>Organ transplantation is the preferred treatment for end-stage organ failure, but the severe shortage of donors severely restricts its clinical application. Xenotransplantation, especially using pigs as donors, is considered an ideal source of alternative donors due to the high similarity between their organ structures and those of humans. However, significant differences in immune recognition and coagulation regulation between species can easily induce a series of rejection reactions, including hyperacute rejection, acute humoral rejection, T-cell-mediated rejection, and chronic vascular complications. It also carries risks such as physiological metabolic incompatibility and potential viral transmission. In recent years, with the development of tools such as CRISPR/Cas, precise multi-gene editing technology has become possible, enabling the simultaneous knockout of multiple xenoantigen genes (such as GGTA1, CMAH, and B4GALNT2) and the introduction of human genes regulating complement, coagulation, and immune responses (such as hCD55, hTBM (THBD), and hCD47), significantly improving the immune tolerance and physiological compatibility of donor organs. This article systematically reviews the immune and coagulation barriers in xenotransplantation, focusing on precise multi-gene editing strategies for pigs used in xenotransplantation. It highlights editing pathways such as tandem knock-in at the same site, simultaneous multi-site editing, stepwise modular editing, and homology-directed repair (HDR) enrichment. Combined with representative organ-specific examples (heart, kidney, liver, and lung), including key non-human primate studies and early human exploratory cases where available, it explores the application prospects of these strategies in creating safe clinical-grade donor pigs and promoting the clinical translation of xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 2","pages":"e70128"},"PeriodicalIF":4.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}