Animal Molecular Breeding 2024, Vol.14, No.1, 106-118 http://animalscipublisher.com/index.php/amb 114 7.2 Potential breakthroughs in immune-compatible organ engineering The field of xenotransplantation is on the cusp of several potential breakthroughs that could revolutionize organ transplantation. One promising approach is the generation of humanized organs in pigs through interspecies blastocyst complementation. This method involves creating pig embryos deficient in specific developmental genes and complementing them with human induced pluripotent stem cells (hiPSCs) to generate organs with human endothelium, thereby reducing the risk of immune rejection (Das et al., 2020). Another significant breakthrough is the creation of genetically modified pigs with multiple gene edits, including the knockout of xenoantigens and the insertion of human transgenes. These modifications have shown promising results in preclinical studies, with some xenografts demonstrating long-term survival and function in non-human primates without signs of hyperacute rejection (Ma et al., 2020; Montgomery et al., 2022). These advancements suggest that genetically engineered pigs could soon provide a viable and sustainable source of organs for human transplantation. 7.3 Collaboration between researchers, clinicians, and policymakers The successful translation of xenotransplantation from preclinical research to clinical practice will require close collaboration between researchers, clinicians, and policymakers. Researchers must continue to refine genetic engineering techniques and conduct rigorous preclinical studies to ensure the safety and efficacy of genetically modified pig organs (Li et al., 2021; Lei et al., 2022). Clinicians will play a critical role in designing and implementing clinical trials, as well as in managing the complex immunological challenges associated with xenotransplantation (Sykes and Sachs, 2019; Montgomery et al., 2022). Policymakers must establish clear regulatory frameworks to oversee the ethical and safe use of xenotransplantation in humans. This includes addressing concerns related to zoonotic disease transmission, long-term graft survival, and patient safety (Wolf et al., 2019; Xi et al., 2023). By fostering interdisciplinary collaboration and creating supportive regulatory environments, the potential of xenotransplantation to alleviate the organ shortage crisis can be fully realized. In conclusion, the future of xenotransplantation looks promising, with emerging technologies and potential breakthroughs offering new hope for patients in need of organ transplants. Continued collaboration between all stakeholders will be essential to overcome the remaining challenges and bring this innovative solution to clinical reality. 8 Concluding Remarks The advancements in genetic modifications of pigs for xenotransplantation have shown promising results in reducing immune rejection and improving the viability of pig organs in human recipients. Studies have demonstrated that genetically modified pig organs can function effectively in human recipients without signs of hyperacute rejection for extended periods. The use of CRISPR-Cas9 technology has enabled precise genetic modifications, such as the knockout of specific antigens and the insertion of human regulatory genes, which have significantly mitigated immune responses and physiological incompatibilities. These findings underscore the potential of xenotransplantation to address the critical shortage of human organs for transplantation. The knockout of the alpha-1,3-galactosyltransferase gene and the insertion of human complement and coagulation regulatory genes have been pivotal in reducing hyperacute and acute rejection in xenotransplantation. This gene-editing tool has facilitated the creation of pigs with multiple genetic modifications, enhancing the compatibility of pig organs with the human immune system. Initial clinical trials have shown that genetically modified pig kidneys can function in human recipients for up to 54 hours without signs of rejection, indicating the feasibility of this approach. Understanding the immunological barriers and developing strategies to overcome them, such as the deletion of carbohydrate antigens and the expression of human complement regulatory proteins, have been crucial in advancing xenotransplantation. Future research should focus on long-term studies to evaluate the durability and functionality of genetically modified pig organs in human recipients. Additionally, exploring the potential of interspecies chimeras and further refining genetic modifications to address remaining immunological challenges will be essential. Clinical applications will benefit from the development of standardized protocols for genetic modifications and the establishment of regulatory frameworks to ensure the safety and efficacy of xenotransplantation.
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