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":"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":3.8,"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":"Breaking Barriers: Proof of Concept for Selective Coronary Endothelial Decellularization in Whole Porcine Hearts for Xenotransplantation.","authors":"Nicola Pradegan, Saima Imran, Diego Ciccarelli, Tea Lena, Fabio Zanella, Emanuele Cozzi, Gino Gerosa","doi":"10.1111/xen.70142","DOIUrl":"10.1111/xen.70142","url":null,"abstract":"<p><p>The critical shortage of donor hearts and the limitations of current mechanical circulatory support devices underscore the need for alternative strategies to address end-stage heart failure. Selective endothelial decellularization has emerged as a promising approach to reduce graft immunogenicity by removing donor endothelial cells while preserving myocardial architecture, thereby enabling subsequent repopulation with recipient-derived cells. However, this technique has never been applied to an intact porcine heart. This pilot study aimed to develop an ex vivo model for partial decellularization of the coronary vasculature in whole porcine hearts. Four hearts were perfused through the aortic root using a controlled circuit, applying variable concentrations of sodium dodecyl sulfate (SDS) or trypsin, followed by washout solutions including saline, distilled water, or hypothermic Buckberg cardioplegia. Histological and immunofluorescence analyses were performed on coronary arteries and ventricular myocardium to assess endothelial removal and tissue preservation. Across all experiments, SDS perfusion achieved effective qualitative and quantitative endothelial decellularization of large-caliber coronary arteries while maintaining the integrity of the internal elastic lamina, extracellular matrix, and myocardial structure. The hypothermic cardioplegic washout protocol demonstrated the highest efficacy, with marked loss of endothelial nuclei and decreased expression of CD31, without evidence of myocardial cell depletion. These findings provide preliminary evidence that selective endothelial decellularization of whole porcine hearts is feasible using SDS under controlled hypothermic conditions. This model may represent an essential step toward generating immunologically compatible xenogeneic hearts through subsequent autologous endothelial repopulation. Further studies are required to standardize the protocol, evaluate microvascular compartments, and explore effective recellularization strategies.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70142"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007026","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":3.8,"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":"The Therapeutic Potential of Complement Inhibitors in Xenoreactive Human Complement-Dependent Cytotoxicity in Vitro.","authors":"Krish Vasudev, Maho Terashita, David K C Cooper, Akihiro Maenaka","doi":"10.1111/xen.70146","DOIUrl":"10.1111/xen.70146","url":null,"abstract":"<p><strong>Background: </strong>Complement activation is critical in xenograft rejection, but the relative efficacy of pharmacological complement inhibitors remains unclear.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells (PBMCs) from wild-type (WT) pigs were exposed to human serum in the presence or absence of complement inhibitors. Complement-dependent cytotoxicity (CDC) and complement deposition were measured by flow cytometry. A C1s inhibitor (sutimlimab, 12.5-800 µg/mL), a C1-esterase inhibitor (berinert, 1.25-10U/mL), a C3/C3b inhibitor (pegcetacoplan, 0.25-4.0 mg/mL), and a C5 inhibitor (tesidolumab, 500-800 µg/mL) were applied to dose-response assays.</p><p><strong>Results: </strong>Only pegcetacoplan (C3/C3b inhibitor) achieved complete inhibition of CDC with minimal C3b/iC3b and C5b-9 deposition. Sutimlimab (C1s inhibitor) produced partial inhibition of CDC (hitting a plateau) and complement deposition, while C1-esterase inhibitor had limited CDC effect and did not reduce C3b/iC3b. Tesidolumab (C5 inhibitor) suppressed C5b-9 but failed to prevent CDC or upstream opsonization.</p><p><strong>Conclusions: </strong>Although these results might reflect experiments conducted at concentrations lower than clinical doses, our data suggest that, of the limited number of agents tested, pegcetacoplan may be the most effective in inhibiting xenoreactive human complement activation in this experimental setting (i.e., CDC of human complement in the pooled-serum against WT pig PBMCs). However, the results we obtained are puzzling because the C5 inhibitor, eculizumab, has been proven to be highly effective in inhibiting human complement activation in the in vitro CDC model. Furthermore, tesidolumab was reported to be effective in an in vivo NHP model. To obtain the additional information required for clinical application, further investigation would be needed. We would need to (i) ensure that the tesidolumab we were using had not deteriorated in any way and lost its efficacy, and (ii) compared pegcetacoplan with other C5 inhibitors (e.g., ravulizumab, eculizumab).</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70146"},"PeriodicalIF":4.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148144703","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":"What's Hot and What's New in Xenotransplantation From the Young Investigator Committee of the IXA-Basic and Translational Science.","authors":"Corbin E Goerlich, Evelyn J Salvaris, Konrad Fischer, Antonio Citro, Alessia Giarraputo, Joseph Ladowski, Emilien Seizilles de Mazancourt, Liaoran Wang, Daniel Eisenson, Margaret R Connolly, Jeffrey Stern, Alban Longchamp, Raphael P H Meier","doi":"10.1111/xen.70150","DOIUrl":"10.1111/xen.70150","url":null,"abstract":"<p><p>Xenotransplantation has been iteratively improved over the last decade in pre-clinical models, with first-in-human clinical trials underway. The 2025 IXA Congress in Geneva was held in parallel with meetings involving World Health Organization leaders to support the development of new guidance on xenotransplantation in this rapidly evolving field. Key scientific themes of the meeting included the introduction of multiple-gene edited pigs for xenotransplantation research and clinical trials, better characterization of innate and adaptive immune responses and xenograft preservation that optimizes ramifications of ischemia-reperfusion injury during implantation. This comes at a time when gene-edited pig organs are being used for human xenotransplantation, a development that demands safety, reproducibility, durability, and a clear mechanistic understanding of rejection and tolerance.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70150"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13266277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148253553","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":"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":"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":3.8,"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":3.8,"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":"Early Experimental Report of the First 8-Gene-Edited Pig-to-Rhesus Macaque Cardiac Xenotransplantation in China.","authors":"Xianzhi Wang, Xijie Wu, Ziqiang Dai, Licheng Yan, Jie Yan, Dongsheng He, Shangxuan Li, Zhipeng Ren, Gen Zhang, Guanzheng Cui, Xin Li, Xianhua Li, Yulong Guan, Guangyu Pan, Ik Jin Yun, Wensheng Zhou, Dengke Pan, Dianyuan Li","doi":"10.1111/xen.70137","DOIUrl":"10.1111/xen.70137","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to investigate the functional recovery of an 8-gene-edited pig heart after orthotopic xenotransplantation, the characteristics of the recipient's immune responses, and the efficacy of postoperative complication management to provide comprehensive experimental evidence for the clinical translation of xenogeneic cardiac transplantation technology.</p><p><strong>Methods: </strong>On December 27, 2025, an orthotopic heart was xenotransplanted from an 8-gene-edited pig to a rhesus macaque using the biatrial anastomosis technique. Postoperatively, comprehensive vital sign monitoring, immunosuppressive therapy, and complication interventions were implemented. Donor organ cardiac function, recipient immune indicators, and survival status were evaluated within 30 days after transplantation.</p><p><strong>Results: </strong>The recipient macaque survived for more than 30 days postoperatively. The cardiac function of the donor heart gradually stabilized, with the ejection fraction increasing from 58% in the early postoperative phase to 66%. No hyperacute immune rejection occurred. Postoperative complications, including infection, pleural effusion, and blood pressure fluctuations, were effectively controlled with symptomatic treatment.</p><p><strong>Conclusions: </strong>An 8-gene-edited pig heart demonstrates good biocompatibility in xenogeneic cardiac transplantation. Standardized surgical procedures, precise immunosuppressive regimens, and comprehensive postoperative care can effectively ensure desirable transplantation outcomes. This study offers an important technical reference for clinical xenogeneic cardiac transplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 3","pages":"e70137"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13161745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147875911","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":"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":3.8,"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}