International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 177 Feature Review Open Access Genetic Determinants of Long-Term Graft Survival in Pig-to-Human Xenotransplantation Xiaofang Lin Tropical Animal Medicine Center, Hainan Institute of Tropical Agricultural Resources, Sanya, 572024, Hainan, China Corresponding email: xiaofang.lin@hitar.org International Journal of Molecular Medical Science, 2024, Vol.14, No.3 doi: 10.5376/ijmms.2024.14.0021 Received: 15 May., 2024 Accepted: 18 Jun., 2024 Published: 28 Jun., 2024 Copyright © 2024 Lin, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Lin X.F., 2024, Genetic determinants of long-term graft survival in pig-to-human xenotransplantation, International Journal of Molecular Medical Science, 14(3): 177-192 (doi: 10.5376/ijmms.2024.14.0021) Abstract Xenotransplantation technology, with its potential contribution to addressing the human organ shortage, is gradually becoming a hotspot in medical research. This study focuses on analyzing the genetic factors affecting the long-term survival of xenografts, with a particular emphasis on reducing immune rejection responses and enhancing graft-host compatibility through genetic modification. The application of CRISPR/Cas9 technology allows for the precise knockout of porcine antigens such as GGTA1, CMAH, and β4GalNT2, as well as the introduction of human complement regulatory proteins like CD46, CD55, and thrombomodulin, which have shown significant effectiveness in mitigating rejection reactions. Additionally, this study extensively discusses the technical, ethical, and regulatory challenges faced by xenotransplantation technology and emphasizes the necessity of interdisciplinary research and collaboration. This research not only provides a scientific basis for the clinical application of xenogeneic organ transplantation but also has profound implications for promoting interdisciplinary cooperation, fostering in-depth discussions on medical ethics, and enhancing public understanding of biotechnological applications. Keywords Xenotransplantation; Genetic modifications; Graft survival; Immunosuppression; Pig-to-human transplantation; Gene editing 1 Introduction Xenotransplantation, the process of transplanting organs, tissues, or cells from one species to another, is an innovative approach to addressing the acute shortage of human organs available for transplantation. The most prominent focus in xenotransplantation research has been on pig-to-human transplants due to the anatomical and physiological similarities between pigs and humans. These similarities make pigs an ideal source for organs such as kidneys, hearts, and livers, which are in high demand for transplantation. The significance of xenotransplantation lies in its potential to drastically reduce the waiting time for organ transplants. Currently, many patients die while waiting for suitable human donors. Xenotransplantation offers a virtually unlimited supply of donor organs, which could meet the growing demand and save countless lives. Additionally, it provides a consistent and controlled source of organs, which can be genetically modified to reduce the risk of rejection and improve compatibility with human recipients (Cooper et al., 2020). Pigs are particularly suitable for xenotransplantation for several reasons. Firstly, pigs have large litters and short gestation periods, making them readily available and easy to breed. Secondly, the size and function of pig organs are similar to human organs, which facilitates the transplantation process. Furthermore, advancements in genetic engineering have enabled scientists to modify pig genomes to remove or alter genes that trigger immune responses in humans. This genetic modification helps in reducing the risk of hyperacute rejection, a major barrier in xenotransplantation (Tatapudi and Griesemer, 2022). The potential benefits of xenotransplantation extend beyond individual patient outcomes. It also has significant implications for public health and the healthcare system. By providing a steady supply of organs, xenotransplantation can alleviate the burden on the healthcare system associated with long-term dialysis for kidney failure patients or the extensive medical management required for patients with end-stage organ failure.
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