Xenotransplantation最新文献

{"title":"Porcine Expanded Potential Stem Cells as a Versatile Platform for Multiplex Genome Editing and Immunophenotyping in Xenotransplantation.","authors":"Yiyi Xuan, Yong Xiang, Xining Wang, Björn Petersen, Pentao Liu","doi":"10.1111/xen.70161","DOIUrl":"https://doi.org/10.1111/xen.70161","url":null,"abstract":"<p><p>Xenotransplantation utilizing pig donors offers a promising solution to organ shortages, but immune incompatibilities across species remain a major challenge. Current reliance on porcine primary fibroblasts for genome editing is limited by low inefficiency in complex gene editing and difficulties in immunophenotyping edited cells. In this study, we demonstrate that porcine expanded potential stem cells (pEPSCs), derived from preimplantation embryos, provide a robust and versatile platform for generating donor cells for xenotransplantation. These pluripotent cells can differentiate into both embryonic and extraembryonic lineages, maintain genetic stability through multiple edits, and enable precise genome modifications. We performed multiple gene knockouts in pEPSCs targeting key immune rejection genes and precisely inserted a genetic cassette to facilitate streamlined introduction of human cDNAs via cassette exchange. The engineered pEPSCs retained their pluripotency and stability even after multiple rounds of genome editing. When differentiated into endothelial cells, they exhibited high immunogenicity, serving as a rapid and quantitative platform for immune response assessment. Importantly, the edited endothelial cells exhibited substantially reduced immunogenicity, confirming the functional impact of the genetic modifications. Although we have not yet generated live pigs from these gene-edited pEPSCs via somatic cell nuclear transfer (SCNT), our findings establish pEPSCs as a novel and improved platform for generating genetically engineered pig donors and for functionally evaluating genetic modifications, thereby advancing the prospects of xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70161"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798604","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":"Beyond the Transplanted: Who Should Inform Attitudes Toward Xenotransplantation?","authors":"Jenny L McDonnell, Tony O Pomales, Tomohiro Tanaka","doi":"10.1111/xen.70159","DOIUrl":"10.1111/xen.70159","url":null,"abstract":"","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70159"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148593534","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":"Combined Islet and Kidney Xenotransplantation for Diabetic Nephropathy: Investigation of Pre-Vascularized Composite Grafts versus Sequential Islet-After-Kidney Transplantation in a Pig-to-Nonhuman Primate Model of Xenotransplantation.","authors":"Alexander C Schulick, Daniel L Eisenson, WeiLi Chen, Wanxing Cui, Kasra Shirini, Yu Hisadome, Saghar Babadi, Michelle Santillan, Kristy Koenig, Du Gu, David H Sachs, Rita Bottino, Xiaojuan Chen, Yuki Cui, Zhoali Sun, Daniel Warren, Akira Shimizu, Hayato Iwase, Kazuhiko Yamada","doi":"10.1111/xen.70153","DOIUrl":"https://doi.org/10.1111/xen.70153","url":null,"abstract":"<p><strong>Aims: </strong>Combined renal and islet xenotransplantation could provide a durable treatment for end-stage diabetic nephropathy. In this feasibility-focused study, we evaluated two complementary approaches for clinical translation: (1) pre-vascularized composite islet-kidney (I-K) grafts and (2) sequential islet-after-kidney xenotransplantation with vascularized thymic lobe (VTL) co-transplantation as an adjunct immune tolerance strategy.</p><p><strong>Methods: </strong>Composite I-K grafts were generated in nine MHC-matched, minor-antigen-mismatched miniature swine pairs by implanting adult porcine islets beneath the renal capsule of juvenile kidney donors followed by pre-vascularization under tacrolimus-based immunosuppression. Separately, three baboons underwent GalTKO.hCD55 kidney and VTL xenotransplantation, followed by streptozocin-induced diabetes and intraportal adult porcine islet infusion from a separate donor. Renal/metabolic function, porcine C-peptide, histology, and immune profiling were assessed.</p><p><strong>Results: </strong>Composite I-K grafts demonstrated limited islet survival with peri-islet inflammation on histology at the graft preparation stage and were not advanced to pig-to-NHP xenotransplantation in this study. Sequential islet-after-kidney transplantation restored insulin-independent euglycemia in all recipients. Porcine C-peptide was detectable in the long-term survivor with intrahepatic insulin-positive islets at necropsy. Infection-associated thrombotic microangiopathy limited survival in two animals; in the 180-day survivor, anti-porcine hypo-responsiveness and evidence of thymopoiesis within the VTL graft were observed.</p><p><strong>Conclusions: </strong>In this limited series, sequential islet-after-kidney xenotransplantation restored metabolic control and represents a promising translational strategy for diabetic nephropathy.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70153"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391835","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 Potential Role of Expression of HLA-E and HLA-G in Organ Xenotransplantation.","authors":"Jeffrey K Sumbo, Xiaowei Hu, Eckhard Wolf, David K C Cooper, Leo H Buhler","doi":"10.1111/xen.70155","DOIUrl":"10.1111/xen.70155","url":null,"abstract":"<p><p>Xenotransplantation offers a promising solution to the shortage of human organs for transplantation but requires overcoming numerous immune responses-particularly those mediated by the innate immune system through natural killer (NK) cells and macrophages. This review examines advances demonstrating that the expression of human leukocyte antigen E (HLA-E) on porcine cells contributes to reduce cellular xenograft rejection. HLA-E expression partially inhibits both direct NK cell cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC), while also attenuating macrophage-mediated lysis. Furthermore, perfusion of transgenic porcine organs expressing HLA-E with human blood resulted in significantly less tissue damage compared to wild-type counterparts, thereby confirming the protective effect of HLA-E against innate immunity. Inhibition of NK cell activation can be further enhanced by co-expression of HLA-G and HLA-E. These findings confirm the potential of HLA-E and HLA-G expression as a complementary strategy in the design of immune-compatible porcine organs for clinical xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70155"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670514","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":"Ethical Considerations in Islet Xenotransplantation.","authors":"Daniel J Hurst, Alexa Tarzy, Christopher A Bobier, Luz A Padilla, Johannes Kögel, Anthony Merlocco, Raphael P H Meier","doi":"10.1111/xen.70152","DOIUrl":"10.1111/xen.70152","url":null,"abstract":"<p><p>For the management of type 1 diabetes, islet xenotransplantation has emerged as a potential alternative to lifelong insulin therapy or islet allotransplantation. However, this progress raises significant ethical questions that warrant further exploration. This article will examine the ethical landscape of islet xenotransplantation, highlighting points of convergence and distinction with solid organ xenotransplantation. We focus on four key areas: (i) animal welfare, including the ethical implications of sourcing large numbers of pigs per recipient; (ii) pediatric considerations, given the lifelong impact of early interventions, and the increasing prevalence and burden of pediatric diabetes; (iii) informed consent and obligations for long-term monitoring including sample retention; and (iv) strategies for inclusive public and patient engagement to build trust and transparency.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70152"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388197","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 Organ Transplantation: What Have We Learned So Far?","authors":"David K C Cooper, Hidetaka Hara, Zuhui Pu, Lisha Mou","doi":"10.1111/xen.70147","DOIUrl":"https://doi.org/10.1111/xen.70147","url":null,"abstract":"<p><p>Since January 2022, eleven clinical xenotransplants into living patients involving gene-edited pig hearts (n = 2) or kidneys (n = 9) have provided initial data on patient selection, organ sourcing, and immunosuppression. Lessons from cardiac cases indicate that (i) patient selection must prioritize candidates with a realistic recovery potential from preexisting debility, (ii) immunosuppressive regimens should be initiated 5-7 days pretransplant to ensure therapeutic blood levels, (iii) the administration of products that potentially contain anti-pig antibodies should be avoided, and (iv) highly sensitive assays are essential to ensure the graft is free of pathogenic microorganisms. In renal cases, evidence suggests that (i) pig organs with multiple gene edits may provide superior protection against the human immune response, and (ii) while immunosuppression targeting the CD40/CD154 co-stimulation pathway effectively prevents the adaptive immune response, it currently fails to eliminate the development of thrombotic microangiopathy or proteinuria. It remains to be determined whether the current gene editing and immunosuppressive protocols are sufficient to enable truly long-term survival of patients and grafts.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70147"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388242","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":"A Review of Informed Consent for Porcine Islet Xenotransplantation to Treat Type 1 Diabetes.","authors":"Jennifer Kovalcik, Sheetal Mohanty, Mairead Higgins, Daniel J Hurst","doi":"10.1111/xen.70158","DOIUrl":"10.1111/xen.70158","url":null,"abstract":"<p><strong>Purpose: </strong>The objective of this review is to map and synthesize the existing literature regarding informed consent for porcine islet xenotransplantation for the treatment of Type 1 Diabetes.</p><p><strong>Methods: </strong>The search was conducted in May 2025 through the following databases: PubMed, SCOPUS, EMBASE, and CINAHL. Broad search strings were used to combine the text words \"islet\" AND \"xenotransplantation\" AND \"consent\" or similar permutations and combinations. Peer-reviewed articles were included if they were published between January 1990 and May 2025 and written in English. The final search results were manually exported to a reference manager system (Zotero), and the PRISMA-ScR flow diagram was created to depict the data extraction process.</p><p><strong>Results: </strong>From 134 sources, 7 articles met eligibility for this scoping review. Although clinical studies have been sporadically conducted, there is a lack of literature describing informed consent for islet xenotransplantation.</p><p><strong>Conclusion: </strong>This review highlighted a scarcity of scholarly discourse and published guidance on informed consent specifically in the context of islet xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70158"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148593553","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":"Perspectives of Patients on the Kidney Transplant Waitlist Regarding Willingness to Undergo Xenotransplantation.","authors":"Joseph M Ladowski, Isabel DeLaura, Imran J Anwar, Isaac Alderete, Haley Humphries, Scott Sanoff","doi":"10.1111/xen.70156","DOIUrl":"10.1111/xen.70156","url":null,"abstract":"<p><strong>Background: </strong>Xenotransplantation, the use of genetically modified pigs as organ donors, is entering clinical trials in kidney transplantation. Although the medical community has long considered xenotransplant a potential solution to the organ shortage, the perspective of potential recipient's is not well described.</p><p><strong>Methods: </strong>We distributed a survey to patients > 18 years of age on our kidney transplant waitlist assessing the following: demographics, insurance status, current waitlist status, transplant history, knowledge of xenotransplantation and recent xenotransplant news, willingness to accept a xenokidney, and reservations regarding xenotransplantation. Surveys were administered through three different modalities: email, electronic medical record patient portal, and physical mailings. A total of 717 patients were surveyed between April and June 2024. Quantitative statistical analysis was performed as well as sentiment and thematic analysis of free-text responses.</p><p><strong>Results: </strong>Of 717 eligible individuals, 79 responses were received (response rate 11%), 59% were electronic and 41% were sent through physical mail. Respondents were 42% female, 25% African American, 85% with at least some college education, 46% with public insurance, and 58% reported religion as very important. Most respondents noted some awareness of xenotransplantation (77%) and many expressed a favorable impression (62%). Survey modality demonstrated a racial difference in response, with African American patients more likely to respond via physical mail (p = 0.014). Overall, the majority of respondents expressed a willingness to accept a xenokidney if outcomes were comparable to allografts (81%) or as a bridge to allotransplantation (65%), with similar findings on the sentiment and thematic analysis. The most common concerns expressed included organ rejection and incompatibility (30%), anxiety over the lack of long-term outcome data (25%) and organ durability (20%).</p><p><strong>Conclusions: </strong>Most patients on our kidney transplant wait list reported positive attitudes toward xenotransplantation and were willing to consider it under various circumstances, independent of anticipated time to transplant or reported time on the wait list. Knowledge of recent transplant events appeared to influence patient perceptions of xenotransplant. Using multiple survey methods was important to capture a sample more representative of our waitlist.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70156"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413141","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":"Global Consultation for Clinical Xenotransplantation: International Xenotransplantation Association Consensus and Communiqué Update.","authors":"Wayne J Hawthorne, Eckhard Wolf, Peter J Cowan, Wei Wang, Ik Jin Yun, Paolo Brenner, Greg Korbutt, Raphael P H Meier, Megan Sykes, Léo H Bühler, Linda Scobie, Olga Garkavenko, Hyunil Kim, Daniel J Hurst, Richard N Pierson Iii, Robert Rieben, Manuel Pascual, Nicole Scholes-Robertson, Emanuele Cozzi, Adrián Abalovich, Alexandre Loupy, Hidetaka Hara, Rita Bottino, Burcin Ekser, Muhammad M Mohiuddin, Jay Fishman","doi":"10.1111/xen.70157","DOIUrl":"10.1111/xen.70157","url":null,"abstract":"<p><p>Xenotransplantation has entered a phase of accelerated clinical translation, necessitating renewed international consensus on governance, ethics, safety, and regulatory oversight. In September 2025, the International Xenotransplantation Association (IXA), in partnership with The Transplantation Society (TTS) and with engagement from the World Health Organization (WHO), convened a Global Consultation in Geneva to review, update, and harmonise international guidance for clinical xenotransplantation. This IXA consultation marked the twentieth anniversary of the first WHO Xenotransplantation Advisory Consultation in 2005 and built upon the foundational principles established through the Changsha Communiqué (2008, 2011 and 2018) and subsequent IXA and WHO-led initiatives. Responding to rapid scientific advances, including some defined donor genetic standards, improved immunosuppression, enhanced biosecurity, and strengthened infectious disease surveillance, the IXA undertook an 18‑month, structured, evidence‑based revision process. Seven expert working groups, comprising approximately forty internationally recognised specialists from fourteen countries, reviewed developments across source animal standards and biosecurity, clinical trial design and oversight, immunosuppression and patient management, infectious disease risk and surveillance, ethical and legal frameworks, international governance, and emerging technologies. Draft recommendations were further refined through iterative consultation and plenary deliberation at the in‑person meeting held in Geneva, September 2025. The consultation proposed updated Principles and Recommendations directed to WHO, national regulators, investigators and sponsors, and the IXA/TTS communities. Key elements include proportionate risk benefit assessments, robust donor and recipient surveillance, long‑term biobanking and monitoring, transparency and public engagement, harmonised regulatory oversight consistent with existing allotransplantation frameworks, and equitable access to future clinical applications. The revised guidance aligns with contemporary regulatory expectations of major international jurisdictions regulatory authorities including (AEMPS, ANMAT, CONABIA, CONFEPRIS, EMA, FDA, GTAC, HC, IEC, INCUCAI, Medsafe, MFDS, MHRA, MHLW, NMPA, NZGTAC, MFDS, MHRA, TGA); and consolidates international consensus at a critical juncture for the field. This IXA Global Consultation provides an authoritative, forward‑looking framework to support safe, ethical, and globally coordinated clinical xenotransplantation as it transitions from experimental innovation to regulated clinical practice.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70157"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670485","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":"Cellular Dynamics of Transgenic Porcine Endothelial Cells to Inflammatory Stimuli in Xenotransplantation Settings.","authors":"Mitra Gultom, Nina Thomi, Kassandra Teixeira-Riberio, Jane Shaw, Alain Despont, Nikolai Klymiuk, Elisabeth Kemter, Eckhard Wolf, Robert Rieben","doi":"10.1111/xen.70149","DOIUrl":"10.1111/xen.70149","url":null,"abstract":"<p><p>Inflammatory responses have been shown to contribute significantly to the rejection of grafts in both allo- and xenotransplantation. In particular, they play a pivotal role in promoting endothelial activation, complement deposition, and thrombosis, thereby compromising the graft function. In this study, we investigated the molecular and functional properties of genetically modified porcine aortic endothelial cells (PAECs) that carry a knockout of α1,3-galactosyltransferase and express human CD46 and thrombomodulin (3GM) in xenogeneic and inflammatory environments. Transcriptomic profiling revealed that these genetic modifications effectively reduced the intrinsic inflammatory and procoagulant phenotype of 3GM PAECs. Under xenogeneic activation, 3GM PAECs also exhibited minimal cellular responses distinct from those of wild-type (WT) PAECs, along with robust protection from the activation of the complement and coagulation systems. However, under inflammatory conditions, 3GM and WT PAECs showed more aligned transcriptional and functional profiles characterized by pronounced upregulation of proinflammatory and prothrombotic pathways, increased complement deposition, and a shift toward a more procoagulant state. This loss of protection during inflammatory conditions was associated with the induction of inflammatory and procoagulant mediators, including PAI-1 and uPAR, despite stable transgene expression. Collectively, these insights enhance our understanding of the complex interplay between inflammation, complement, coagulation, and immune regulation in xenotransplantation. Our findings further emphasize the importance of incorporating both genetic and pharmacologic strategies targeting inflammatory pathways to enhance graft compatibility.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"33 4","pages":"e70149"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346017","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}