Introduction: Xenotransplantation of the heart holds promise as a potential therapy for individuals with advanced heart failure; however, the availability of organs from human donors must align with the clinical need. Consequently, xenotransplantation utilizing genetically engineered porcine hearts emerges as a plausible alternative. To date, investigations have examined pig-to-monkey heart xenografts employing multi-transgenic pigs, revealing diverse survival durations alongside transcriptomic alterations within the cardiac tissue. Nevertheless, the functional alterations in other tissues resulting from heart xenotransplantation remain uncertain. The objective of this study was to elucidate the transcriptomic mechanisms occurring in other tissues subsequent to pig-to-monkey xenotransplantation.
Method: A heterotopic abdominal transplantation procedure was conducted utilizing a CD46-expressing GTKO pig as the donor and a cynomolgus monkey as the recipient. We obtained the (recipient) heart, aorta, liver, and lung tissues from both a normal cynomolgus monkey and a cynomolgus monkey that survived for 60 days post-operation. RNA was extracted from all obtained tissues, followed by sequencing. Then, we conducted a transcriptomic comparison between the tissues from the xenotransplanted monkey and those from the normal monkey. Functional annotation based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases was conducted for the differentially expressed genes (DEGs) identified in each tissue.
Results: Respectively, 1793, 1085, 4475, and 3133 DEGs were identified in the heart, aorta, liver, and lung tissues. Both the heart and aorta displayed a multitude of functions linked to lipid metabolism and immune signaling. The liver exhibited alterations primarily centered around lipid metabolism, whereas the lung displayed alterations primarily centered around immune signaling.
Conclusion: These findings showed that heart xenotransplantation elicits alterations in lipid metabolism and immune signaling across other organs. Hence, significant adverse effects are expected to manifest not only in the target organ but also in non-target organs within xenotransplantation research, underscoring the imperative for additional investigation.