Spatial transcriptomic analysis on the liver of pig-to-NHP islet transplantation recipient reveals increased adipogenesis and non-alcoholic fatty liver disease pathway in early post-transplantation
Yoonji Bang1, Hyunwoo Chung1, Byoung-hoon Min3, Jun-Seop Shin3, Ji-Hyun Lee1, Jong-Min Kim3,4, Hyun-Je Kim1,2,3,4,5, Chung-Gyu Park1,2,3,4.
1Department of Biomedical Sciences, Seoul National University, Seoul, Korea; 2Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Korea; 3Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea; 4Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; 5Seoul National University Hospital, Seoul, Korea
Pancreatic islet transplantation is one of the best therapeutic options for type 1 diabetes patients with glycemic lability and hypoglycemia unawareness. Due to donor organ shortage, pig-to-human islet xenotransplantation is expected to be the ultimate beta cell-replacement therapy with substantial preclinical results to support this claim. The liver is the site of preclinical porcine islet transplantation as well as allogeneic clinical transplantation, yet there has been a lack of understanding of the pathology of the liver after the transplantation procedure and during immunosuppressive maintenance. Due to our observation of peri-portal hepatocyte dynamics in primate models post-transplantation, we have performed a retrospective study on the hepatic pathology of the pig-to-NHP islet recipients with short-term graft survival by utilizing recently developed spatial transcriptomic analyses to dissect transcriptomic changes in situ. Spatial transcriptomic analysis revealed a significant increase in adipogenesis and non-alcoholic fatty liver disease pathways (NAFLD), including upregulated expression of SREBF1, CEBPA, IGF1, and TNFRSF12A. Activation of the mTORC1 pathway by insulin increases the production of SREBF-1, which promotes the storage of fatty acids in the form of triglycerides. SREBF-1 also interacts with C/EBP-α, and C/EBP-α can stimulate the expression of IGF-1, which is one of the inducers that activates adipocyte differentiation. Moreover, on 33 days post-transplantation, while the severity of the white multifocal lesion showed a reduction in the gross examination, fatty liver disease and non-alcoholic steatohepatitis (NASH) signature genes were still shown at the transcription level. Our results confirmed that fatty liver disease-causing genes are upregulated in post-transplantation of pig-to-NHP islet transplantation recipients and suggested a clue as to what causes the hepatic pathology during islet transplantation.
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