Spatial transcriptomic analysis reveals increased adipogenesis and non-alcoholic fatty liver disease pathway in pig-to-NHP islet transplantation recipient liver during early post-transplantation period

Pancreatic islet transplantation stands out as a promising therapeutic avenue for type 1 diabetes patients grappling with glycemic instability and hypoglycemia unawareness. Given the persistent scarcity of donor organs, there is growing anticipation that pig-to-human islet xenotransplantation will emerge as the definitive beta cell replacement therapy for this condition. The liver is the site of preclinical pig-to-NHP islet transplantation as well as allogeneic clinical transplantation, yet there's still a lack of understanding on the pathology of the liver after the transplantation procedure. Based on our observations of post-transplantation periportal pathologic changes in primate models, we have conducted a retrospective study examining the hepatic pathology in pig-to-NHP islet recipients with short-term graft survival, employing a state-of-the-art spatial transcriptomic platform within the vicinity of the islet implantation site. Post-transplantation liver tissue could be easily distinguished into three regions based on transcriptional profiles, consistent with its histology. A notable elevation in adipogenesis and non-alcoholic fatty liver disease (NAFLD) pathways could be identified, which included increased expression of SREBF1, CEBPA, IGF1, and TNFRSF12A. We furthermore discovered that, despite the decreased severity of the multifocal white lesions indicated by gross examination at 33 days post-transplantation, there was still evidence of NAFLD at the transcriptional level. These results prompt further research into the relationship between intrahepatic islet transplantation and hepatic microenvironment. Overall design: A total of 18 AOIs were categorized into three groups as follows: steatohepatitic area and a non-steatohepatitic area on DPT8, as well as the recovered area on DPT33.