Spatial Transcriptomic Analysis Reveals Increased Adipogenesis and Triggering of the Non‐Alcoholic Fatty Liver Disease Pathway in Pig‐to‐NHP Islet Recipients’ livers During the Early Post‐xenotransplant Period

ABSTRACT 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 its pathology following islet transplantation remains poorly understood. 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 demarcated into three transcriptionally distinct regions, consistent with its histology. A notable elevation in adipogenesis and non‐alcoholic fatty liver disease (NAFLD) pathways was observed, exemplified by increased expression of SREBF1 , IGF1 , CEBPA , FASN, GCK , and SCD . 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 fatty liver disease at the transcriptional level. These results warrant further research into the relationship between intrahepatic islet transplantation and the hepatic microenvironment.