International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 177-192 http://medscipublisher.com/index.php/ijmms 188 challenges. These rejections occur due to complex immune responses involving complement activation, coagulation pathways, and cellular immunity, requiring a multifaceted approach to immunosuppression and genetic modification (Montgomery et al., 2022). Another technical challenge is the risk of zoonotic infections. Porcine endogenous retroviruses (PERVs) can potentially be transmitted to human recipients. While genetic modifications to inactivate PERVs have been developed, ensuring the complete safety of xenotransplantation remains a priority (Xi et al., 2023). 9.2 Emerging trends and innovative approaches Emerging trends and innovative approaches are continually evolving to address these challenges. CRISPR/Cas9 technology has revolutionized genetic engineering, allowing precise edits to the pig genome to knock out immunogenic genes and introduce human protective genes. This technology has facilitated the development of pigs with multiple genetic modifications aimed at reducing immunogenicity and enhancing compatibility with the human immune system (Zeng, 2023). Furthermore, the use of chimeric organs, where human cells are introduced into developing pig organs, is an innovative approach to reducing rejection risks. This method aims to create organs that are more human-like in their cellular makeup, potentially improving graft acceptance and function (Cengiz and Wareham, 2019). 9.3 Interdisciplinary research and collaboration opportunities The field of xenotransplantation benefits immensely from interdisciplinary research and collaboration. Collaboration between geneticists, immunologists, transplant surgeons, and bioethicists is essential for advancing the science and addressing the complex ethical and technical challenges. Interdisciplinary efforts have led to significant advancements, such as the development of genetically modified pigs with human-like immune tolerance, and have paved the way for potential clinical applications (Lu et al., 2020). Future research will likely focus on fine-tuning genetic modifications to further reduce immunogenicity and enhance graft survival, as well as developing new immunosuppressive therapies tailored specifically for xenotransplantation. Collaborative networks and research consortia will play a crucial role in facilitating these advancements and ensuring the translation of preclinical findings into clinical practice (Niu et al., 2020). In conclusion, while significant challenges remain, ongoing innovations and interdisciplinary collaborations hold promise for the successful implementation of pig-to-human xenotransplantation, potentially addressing the global shortage of human organs for transplantation. 10 Concluding Remarks The systematic review on genetic determinants of long-term graft survival in pig-to-human xenotransplantation has highlighted several critical insights and findings. Key genetic modifications, such as the knockout of xenoantigens (e.g., GGTA1, CMAH, β4GalNT2) and the introduction of human complement regulatory proteins (e.g., CD46, CD55, thrombomodulin), have shown significant promise in reducing hyperacute and acute vascular rejection. Studies have demonstrated that genetically engineered pigs lacking major immunogenic antigens and expressing human regulatory genes can achieve improved graft survival and function. Furthermore, innovative approaches like CRISPR/Cas9-mediated genetic modifications and the use of chimeric organs have opened new avenues for enhancing graft compatibility and reducing immune rejection. The findings from this study have significant implications for future research and clinical practice. Continued advancements in genetic engineering, particularly through the use of CRISPR/Cas9 technology, will be crucial in creating more refined and effective genetic modifications to improve graft survival. Future research should focus on long-term studies to assess the durability and functionality of genetically modified xenografts in human recipients. Additionally, the development of new immunosuppressive therapies tailored specifically for xenotransplantation is essential to manage immune responses and enhance graft longevity. Collaborative efforts across disciplines, including genetics, immunology, and transplantation surgery, will be vital in driving these advancements forward.
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