Xenotransplantation最新文献

Xenotransplantation has garnered significant attention in recent years, characterized by substantial progress and rapid developments within the field. The objective of this study was to investigate the evolving trends and emerging research hotspots in xenotransplantation through a comprehensive bibliometric analysis. We conducted an analysis of literature published between 1980 and 2025, sourced from the Web of Science Core Collection. Data processing, analysis, and visualization were performed using VOSviewer, CiteSpace, the Bibliometric R package, and Scimage Graphica. A total of 7880 articles spanning 45 years were included in the analysis. The United States emerged as the predominant contributor to the field, both in terms of article output and institutional involvement. Professor David K. C. Cooper was identified as the leading author, with the highest number of publications on xenotransplantation. The journal Xenotransplantation was found to be the most prolific in terms of article publication. Key research hotspots identified through this analysis include the selection of gene-editing strategies for pigs, the use of genetically modified pigs as donors for various cells, tissues, and organs, as well as the focus on clinical trials and translational studies aimed at advancing xenotransplantation.

Background: Xenotransplantation, using gene-edited pigs, represents an important approach to overcoming human organ shortages. A major obstacle to xenotransplantation is antibody-mediated rejection (AMR), which leads to xenograft injury by activating complement and effector cells through the fragment crystallizable domain (Fc) of donor-specific antibodies (DSAs). Therefore, we designed a strategy to express the human high-affinity IgG receptor (hCD64) on porcine endothelial cells to competitively bind IgG and protect xenografts from AMR.

Methods: The lentiviral transduction of hCD64 into porcine aortic endothelial cells (PAEC) from wild-type and GTKO pigs was validated using quantitative reverse transcription (qRT)-PCR, Western blot, and flow cytometry. The effects of hCD64 transduction and activation on cell physiology were assessed using RNA sequencing. The IgG Fc-binding capacity of hCD64 was validated using flow cytometry and ELISA. Finally, the protective effect of hCD64 against complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in PAECs and GTKO PAECs was confirmed through apoptosis assays.

Results: hCD64 was stably expressed at both mRNA and protein levels in PAEC^hCD64 and PAEC^GTKO/hCD64, with both exhibiting normal physiological functions. PAEC^hCD64 and PAEC^GTKO/hCD64 bound free human IgG in a concentration-dependent manner. In contrast, hCD64 did not bind to human IgM or pig and mouse IgG. In the CDC assay, the survival of PAEC^hCD64 was significantly higher than that of PAEC^NC (67.89% vs. 46.03%); moreover, the survival in GTKO PAEC had the same trend (85.18% vs. 71.09%). Similar results were obtained in the assay of ADCC: the survival rates of PAEC^hCD64 and PAEC^NC were 67.27% and 44.95%, respectively, and the survival of PAEC^GTKO/hCD64 and PAEC^GTKO/NC were 80.73% and 66.62%, respectively. Pre-saturation with high doses of human-derived mAbs did not abrogate the protective function of hCD64.

Conclusion: hCD64 expression may partially protect xenografts from AMR through its ability to bind competitively with DSAs IgG Fc.

Porcine endogenous retroviruses (PERVs) are present in the germ lines of domesticated pigs (Sus scrofa) and related suids. There are three types of PERVs, PERV-A, -B, and -C, which differ in their host range. PERV-A and -B can infect human and porcine cells, while PERV-C only infects porcine cells. PERV-A and -B are found in the genomes of all pigs, while PERV-C is found in most but not all pigs. Although many PERV provirus insertions are defective, in vitro culture of porcine cells has produced infectious virions of all three types as well as PERV-A/C recombinants, which show enhanced replication competence. Identifying pigs that are PERV-C negative could help prevent such recombination events and would advance the development of porcine germplasm as a safer source of xenografts for humans. Here, we present the results of extensive screening involving 142 Landrace, Duroc, Large White, and crossbred pigs using up to nine primer pairs to identify putative PERV-C-negative animals. Long-read whole genome sequencing was conducted on a subset of four pigs (one PERV-C PCR positive and three PERV-C PCR putative negatives), which confirmed their status as PERV-C positive or negative, respectively. Our results confirmed that the screened pigs were truly PERV-C negative, establishing the existence of PERV-C-negative germplasm within the herd. These findings support the feasibility of developing or selecting PERV-C-negative pigs as a source of germplasm for xenotransplantation and other biomedical applications.

Genetically engineered porcine organs are redefining the boundaries of clinical xenotransplantation. Zhang et al. now report the first functional pig-to-human liver xenotransplantation in a living patient, demonstrating that a 10-gene-edited auxiliary porcine liver can engraft, produce bile, and synthesize metabolic and coagulation factors in vivo. The xenograft supported a high-risk hepatectomy with borderline remnant volume and contributed to early postoperative stability, although xenotransplant-associated thrombotic microangiopathy ultimately required graft removal. The case highlights both the promise of xenogeneic hepatic support and the physiologic limits that currently preclude durable therapy, including thrombocytopenia, complement-coagulation incompatibility, portal-flow competition, and challenges in assessing dual-graft function. These results establish proof-of-concept for temporary porcine liver support in humans and outline key priorities for next-generation designs: optimized thromboregulation, mitigation of xTMA, improved immunomodulation, and strategies for controlled transition to native-liver autonomy.

Background: Porcine islet xenotransplantation is limited by the availability of clinically applicable immunosuppressive regimens. We tested four depletional induction strategies and maintenance regimens in a non-human primate (NHP) islet xenotransplant model.

Methods: Genetically modified or wild-type neonatal porcine islets were transplanted via portal vein infusion in diabetic NHPs. Induction consisted of rhesus anti-thymocyte globulin (rhATG) (Group 1, n = 4), anti-CD4 monoclonal antibody (mAb, Group 2, n = 3), or human anti-thymocyte globulin (huATG) tocilizumab (Groups 3 and 4; n = 3 and n = 4, respectively). Maintenance consisted of B7 (Groups 1-3) or anti-CD154 (Group 4) costimulation blockade, tacrolimus transitioned to sirolimus (sirolimus only in Group 4), and mycophenolate mofetil. Xenografts were monitored for blood glucose and porcine c-peptide.

Results: Median graft survivals were <14 days (Group 1), <14 days (Group 2), 99 days (Group 3), and 119 days (Group 4). Insulin independence was achieved in one animal in Group 4. Graft survival significantly correlated with islet dose >40,000 IEQ/kg. Rejection was predominately CD3⁺ T-cell mediated. Selective depletion of CD4⁺ T cells led to increased proliferation of CD8⁺ T cells and CD8⁺ infiltrates.

Conclusions: Induction with huATG/tocilizumab and maintenance with 5c8 led to the best functional outcomes. CD4 T-cell depletion with anti-CD4 mAb induced compensatory CD8 T-cell proliferation and graft infiltration.

Introduction: Non-invasive biomarkers that detect xenograft injury before irreversible damage are essential for improving kidney xenotransplantation outcomes. This study investigated whether xenograft-derived cell-free DNA (xdcfDNA) is helpful as a non-invasive, early biomarker of antibody-mediated rejection.

Methods: Kidneys from genetically engineered pigs (GGTA1/CMAH/iGb3s/B4GalNT2 knockout; CD39, CD55, CD46, TBM knock-in) were transplanted into 10 cynomolgus monkeys, which received thymoglobulin, rituximab, anti-CD154 monoclonal antibody, corticosteroid, tacrolimus, and mycophenolate mofetil. Plasma xdcfDNA was measured using species-specific quantitative polymerase chain reaction. Pathological scoring and rejection diagnosis of the kidney xenograft biopsy were performed based on the Banff 2022 criteria.

Results: XdcfDNA levels increased markedly before an overt increase in serum levels of creatinine and blood urea nitrogen after kidney xenotransplantation. When recipients were classified into low- and high-score groups based on the Banff score of kidney xenograft biopsy, xdcfDNA levels were higher in the high-score groups for intimal arteritis (v), composite vasculitis (g + ptc + v), tubular atrophy (ct), interstitial fibrosis (ci), and IgG deposition. Furthermore, the rejection group showed higher xdcfDNA levels than the non-rejection group (p = 0.0270). The cut-off xdcfDNA value for xenograft rejection was 2.545%, with an apparent sensitivity of 100% (95% confidence interval, 64.57%-100.00%) and specificity of 100% (43.85%-100.00%).

Conclusions: XdcfDNA is a potentially sensitive, noninvasive, and early biomarker of xenograft rejection, capturing vasculitis and subsequent chronic injury. Periodic monitoring of xdcfDNA could support noninvasive screening of rejection before overt functional changes in xenografts emerge and might contribute to guiding confirmatory xenograft biopsy and subsequent immunosuppression modification.

Purpose: To compare the effectiveness and prognosis of lamellar keratoplasty (LK) using human cornea and acellular porcine corneal stroma (APCS) for noninfectious peripheral ulcerative keratitis (PUK).

Methods: Fifty-eight patients with noninfectious PUK who underwent LK from 2013 to 2023 were included in this retrospective study. Patients were divided into human cornea (n = 27) and APCS (n = 31) groups according to corneal graft material. The primary outcome was best-corrected visual acuity (BCVA) at 1, 3, 6, and 12 months postoperatively. Kaplan-Meier analysis was used to evaluate graft survival rates within 12 months.

Results: BCVA improved in both groups. The human cornea group had better BCVA at 3 months (p = 0.045) and 6 months (p = 0.010) postoperatively, but no significant difference was observed at 1 or 12 months (p > 0.05). Corneal epithelial healing time was similar overall, but prolonged in the APCS group among patients with autoimmune diseases (p = 0.012). The number of transparent corneal grafts was higher in the human cornea group at 1, 3, and 6 months (p < 0.05), but comparable at 12 months (p > 0.05). Complications occurred in 13 APCS patients and 10 human cornea patients (p > 0.05). Graft survival rates were 80.6% for APCS and 88.8% for human cornea at 12 months (p > 0.05).

Conclusion: APCS is a feasible alternative for noninfectious PUK, with promising visual recovery and long-term outcomes. However, its midterm effectiveness may be slightly inferior, especially in patients with autoimmune diseases, suggesting a need for tailored approaches.

Kidney allotransplantation remains the optimal treatment for end-stage renal disease, but the shortage of donor organs is a persistent issue. Xenotransplantation using gene-edited pig kidneys has shown promise in overcoming this limitation. However, there remain hurdles that include ischemic injury during transportation. The impact of prolonged storage on gene-edited porcine kidneys is not well understood, and few studies have evaluated preservation methods under conditions relevant to xenotransplantation. The present review examines various methods of kidney preservation, focusing on their applicability to xenotransplantation. Methods such as static cold storage (SCS), hypothermic machine perfusion (HMP), and normothermic machine perfusion (NMP) each offer advantages and drawbacks. SCS is widely used but can lead to poor outcomes when kidneys are stored for extended periods. HMP improves renal function and reduces ischemia-reperfusion injury but is limited by its low-temperature metabolic restrictions and benefits from oxygenation. NMP, by maintaining kidneys at physiological temperatures, allows for metabolic activity and real-time viability assessment, though it is associated with logistical challenges. Recent studies suggest that for long periods of storage NMP may better preserve kidney function than HMP. Techniques such as supercooling and partial freezing are in their infancy but offer the prospect of long-term preservation. In summary, long-term storage of pig kidneys could become feasible with advances in machine perfusion or supercooling/cryopreservation techniques. If successful, these innovations would enable the global distribution of gene-edited pig kidneys. However, if meaningful results are to be obtained that are relevant to clinical pig kidney xenotransplantation, future preclinical studies need to be much simpler than those carried out in relation to kidney allotransplantation.

Introduction: With the advent of genome editing technology, xenotransplantation has been attracting attention in recent years as a potential solution to the shortage of organs for transplantation. In Japan, several Japanese universities have reportedly been preparing for the first Japanese clinical trial. However, xenotransplantation poses social issues. Therefore, it is necessary to understand the public's awareness and opinions of it, and policymakers and researchers of xenotransplantation must prepare for social issues.

Materials and methods: In December 2024, an online survey was conducted on Japanese aged 20 to 79, asking questions about their awareness, acceptability, and preferred transplant method. IBM SPSS was used for statistical analysis, and correlations with attributes were also examined.

Results: Valid responses were obtained from 3209 people (response rate: 10.8%). Only 34.6% knew the meaning of xenotransplantation, and 53.8% had a favorable opinion about xenotransplantation being performed as a medical treatment in the future. However, 77.0% predicted that they would feel uncomfortable if a doctor suggested xenotransplantation to them, and 60.9% predicted that they would decide not to undergo xenotransplantation. Fifty-eight percent responded that they would be anxious about discrimination, and 88.2% responded that they would be anxious about being infected with animal-derived pathogens if they received a xenotransplant. In addition, only 1.7% ranked xenotransplantation as their first preference.

Conclusion: The results imply the Japanese public is not ready enough to accept xenotransplantation. This study proposes four points that policymakers and researchers should prepare for social issues before the clinical trial begins in Japan.

This survey explored the ethical, legal, and social implications (ELSI) of xenotransplantation in adolescents and young adults. A web-based questionnaire targeting individuals aged 12-30 was conducted via a Japanese government platform. Results from 113 responses revealed generally positive attitudes toward xenotransplantation, particularly among males, and also highlighted concerns about infection, identity, and animal ethics. Most respondents conditionally accepted xenotransplantation, emphasizing informed consent and societal awareness. Xenotransplantation was ranked lowest in treatment priority compared to regenerative medicine and human organ transplantation. The survey captured respondents' feelings about themselves or friends receiving xenotransplants and highlighted issues to address before clinical use in Japan. Findings were presented at a national expert committee meeting, emphasizing the importance of including adolescent and young adults' perspectives in research and review processes. As Japan considers xenotransplantation research under regulation, this survey offers global insights to support ELSI-aligned development.