Aug 2026· Transplantation· 0 citations· 79 references
Medicine
TL;DR
These approaches offer promising strategies to expand the donor organ pool and address the growing global demand for transplantation and will be critical for widespread translation.
Abstract
The persistent shortage of human organs for transplantation has intensified efforts to develop alternative sources, specifically xenotransplantation and exogenesis. Xenotransplantation uses genetically engineered pigs to provide organs, tissues, and cells for clinical use. Significant progress has occurred in developing multigene-modified pigs that lack glycan xenoantigens while expressing human complement and coagulation regulators. These modifications have successfully mitigated hyperacute, antibody-mediated, and cellular rejection in preclinical nonhuman primate models. Recent compassionate-use cases in humans have demonstrated the feasibility of heart, kidney, and liver xenotransplantation, although achieving long-term survival remains a challenge. Complementing this approach, exogenesis aims to generate human-compatible organs within animal hosts through interspecies chimerism. Although advances in establishing organ niches and overcoming xeno-barriers have yielded preliminary success in heart, pancreas, and muscle development, formidable immune and developmental hurdles remain. Together, these approaches offer promising strategies to expand the donor organ pool and address the growing global demand for transplantation. Further advances in genetic engineering, immune modulation, and developmental biology, supported by rigorous preclinical and clinical evaluation, will be critical for widespread translation. This review outlines the current progress, major challenges, and future directions in xenogeneic and exogenic organ generation.
Liver transplantation remains the only definitive therapy for end stage liver disease, yet its application is fundamentally constrained by donor organ scarcity. Despite advances in organ preservation, marginal graft utilization, and xenotransplantation, a scalable source of functional liver tissue has not been realized. Blastocyst complementation has emerged as a novel strategy to generate exogenic organs, enabling the development of human derived hepatocytes within a xenogeneic host. The approach introduces a distinct biological paradigm where human parenchymal cells coexist with partial xenogeneic non-parenchymal compartments, resulting in compartmentalized immunogenicity. Efficient human-porcine blastocyst complementation remains an evolving technology, and functional exogenic humanized livers have yet to be demonstrated in large-animal transplant models. We examine exogenic liver transplantation through an immunology-first, clinical framework with emphasis on early graft injury driven predominantly by innate immune mechanisms at the vascular interface, including complement activation, macrophage mediated clearance, thrombocytopenia, and coagulation dysregulation as a major barrier observed in liver xenotransplantation. While adaptive immune responses may be attenuated due to reduced antigenic burden, residual xenogeneic endothelial and stromal compartments remain critical drivers of immune activation. We highlight exogenic hepatocyte transplantation as a potential translational bridge, enabling functional validation of chimerism-derived human hepatocytes in vivo while bypassing the vascular incompatibility inherent to whole organ transplantation. This cell-based therapy could offer a platform before the clinical realization of whole exogenic liver transplantation. We propose a phased immunomodulatory approach centered on early control of innate and humoral injury using induction therapy, plasmapheresis, and complement modulation, followed by tolerance-oriented tapering of maintenance immunosuppression. Finally, we outline a translational pathway incorporating preclinical validation, ex vivo perfusion, and human decedent transplant models, while addressing ethical, biosafety, and logistical considerations. Exogenic liver transplantation has the potential to represent a transformative strategy to generate scalable, immunologically optimized grafts and redefine the future of liver transplantation.
J. Rao, Anala V. Shetty, Sabarinathan Ramachandran et al.· Cell Transplantation· 0 citations
It is demonstrated that porcine expanded potential stem cells, derived from preimplantation embryos, provide a robust and versatile platform for generating donor cells for xenotransplantation and for functionally evaluating genetic modifications, thereby advancing the prospects of xenotransplantation.
Yiyi Xuan, Yong Xiang, Xining Wang et al.· Xenotransplantation· 0 citations
For patients with end-stage organ dysfunction, organ transplantation is the only viable treatment option. However, the most significant challenge at present is the severe shortage of donor organs, and no technology exists that allows for long-term, sustainable organ generation. The utilization of xenogeneic animals as in vivo bioreactors constitutes a viable method for the generation of functional and transplantable cells, tissues, and organs in vivo. The primary technology, blastocyst complementation, involves the injection of donor pluripotent stem cells into an organogenesis-disabled host embryo. This allows donor stem cells to compensate for organ defects and ultimately generate tissues or organs derived from the donor. Recent advancements in the field have demonstrated the successful generation of xenogeneic tissues and organs in rodents and large animals through the utilization of blastocyst complementation techniques. In addition, the replacement of nephron progenitor cells in the kidneys can be achieved through the application of the organogenic niche method. Furthermore, the expansion of xenogeneic hepatocytes and blood cells in immunodeficient animals is a viable approach. In this review, we introduce the history of blastocyst complementation and the impact of the pluripotent state of stem cells, one of its elements, on chimeric efficiency. Additionally, we provide a synopsis of the research progress concerning the utilization of rodents, pigs, and cattle as in vivo bioreactors to generate xenogeneic cells, tissues, and organs. Finally, the potential opportunities, challenges, and prospects for generating human blood cells in pigs are discussed.
Yunhan Tang, Ye Feng, Zhu Chen et al.· Signal Transduction and Targ...· 0 citations
To meet the global shortage of organs, extensive genome modifications have been performed to “humanize” livestock tissues for xenotransplantation. However, residual immune rejection remains a problem, prompting alternative approaches that explore the use of animals as hosts for growing human organs. This requires genome editing to disable organogenesis in the host and embryo complementation with suitable donor cells to fill the empty organ niche in chimaeric animals. Pigs have been the predominant livestock species investigated for this approach. Here, we used domestic sheep as hosts for donor-derived kidney formation. Spalt-Like Transcription Factor 1 (SALL1) was targeted in male fibroblasts lacking xenoantigens CMAH and GGTA1, using either one gRNA within zinc finger cluster (ZFC) 2 or two gRNAs to remove all ZF domains. Following somatic cell cloning and embryo transfer of triple knockout strains, fetuses were collected on gestational day 48 to analyze the SALL1 KO phenotypes. Single gRNA editing produced a hypomorph with different degrees of metanephric hypoplasia, while the dual-gRNA deletion resulted in a null allele which completely abolished nephrogenesis. Female donor cells carrying high vs low copy numbers of an mCherry transgene, as well as CMAH and GGTA1 edits, were used for morula complementation. Fetal kidney development was anatomically and histologically restored in sex-chimaeric hosts, providing proof-of- concept for using sheep as a new model species for in vivo organ generation.
S. J. Appleby, Lisanne M. Fermin, S. Delaney et al.· bioRxiv· 0 citations
Autologous HSC transplantation does not have the previously mentioned problems associated with allogeneic transplantation, and gene editing involving ex vivo genetic modification of HSCs and subsequent reinfusion in a single patient has emerged.
Qiu Li, Hong-Xia Wang, Yu-Qin He et al.· International journal of hem...· 0 citations
Xenotransplantation using genetically engineered pig organs offers a promising solution to the shortage of donor organs for life-saving transplantations. However, human-preformed antibodies against unknown pig xenoantigens remain a significant barrier to successful xenotransplantation. Current methods for characterizing these antibodies or xenoantigens are limited to cellular-level cross-match assays. In this study, we developed a novel approach to identify pig xenoantigens, including peptide and glycopeptide epitopes, that react with human-preformed antibodies. First, human-preformed antibodies against xenoantigens were enriched from plasma using immobilized pig kidney proteins. The enriched antibodies were then immobilized and used to isolate pig kidney proteins, peptides, and intact glycopeptides, followed by liquid chromatography-tandem mass spectrometry analysis. This dual-level approach identified 221 peptides corresponding to 153 proteins, with a significant enrichment of plasma membrane and extracellular proteins. Notably, 11 peptides were unique to pig sequences, suggesting their potential role in driving xenogeneic immune responses. Glycoproteomic analysis identified 122 intact glycopeptides, predominantly complex/hybrid glycoforms, and Neu5Gc-containing glycans. Our method effectively identifies peptides and intact glycopeptides reactive to human-preformed antibodies, providing critical insights for discovering xenoantigens. These findings could guide genetic engineering strategies and enhance recipient candidate screening for xenotransplantation, ultimately increasing the feasibility and success of xenogeneic organ transplantation.
Hongyi Liu, Trung Hoàng, Ying Hu et al.· Journal of Proteome Research· 0 citations