Comparative transcriptome analysis between long- and short-term survival after pig-to-monkey cardiac xenotransplantation reveals differential heart failure development

다국어 초록 (Multilingual Abstract)

Cardiac xenotransplantation is the potential treatment for end-stage heart failure, but the allogenicorgan supply needs to catch up to clinical demand. Therefore, genetically-modified porcine heartxenotransplantation could be a potential alternative. So far, pig-to-monkey heart xenografts havebeen studied using multi-transgenic pigs, indicating various survival periods. However, functionalmechanisms based on survival period-related gene expression are unclear. This study aimed toidentify the differential mechanisms between pig-to-monkey post-xenotransplantation longandshort-term survivals. Heterotopic abdominal transplantation was performed using a donorCD46-expressing GTKO pig and a recipient cynomolgus monkey. RNA-seq was performed usingsamples from POD60 XH from monkey and NH from age-matched pigs, D35 and D95. GeneannotatedDEGs for POD60 XH were compared with those for POD9 XH (Park et al. 2021). DEGswere identified by comparing gene expression levels in POD60 XH versus either D35 or D95 NH.
1,804 and 1,655 DEGs were identified in POD60 XH versus D35 NH and POD60 XH versus D95NH, respectively. Overlapped 1,148 DEGs were annotated and compared with 1,348 DEGs forPOD9 XH. Transcriptomic features for heart failure and inhibition of T cell activation wereobserved in both long (POD60)- and short (POD9)-term survived monkeys. Only short-termsurvived monkey showed heart remodeling and regeneration features, while long-term survivedmonkey indicated multi-organ failure by neural and hormonal signaling as well as suppressionof B cell activation. Our results reveal differential heart failure development and survival at thetranscriptome level and suggest candidate genes for specific signals to control adverse cardiacxenotransplantation effects.