Guang-Peng Zhou, People's Republic of China has been granted the TTS Scientific Congress Award
Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure
Guang-Peng Zhou1,3, Shi-Peng Li1,3, Yi-Zhou Jiang1,2,3, Jie Sun1,3, Yu-Le Tan1,3, Zhi-Gui Zeng1,3, Lin Wei1,3, Wei Qu1,3, Li-Ying Sun1,2,3, Zhi-Jun Zhu1,3.
1Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China; 2Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China; 3Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, People's Republic of China
Background: Explanted livers from patients with inherited metabolic liver diseases possess the potential to be a cell source of good-quality hepatocytes for hepatocyte transplantation (HT). This study evaluated the therapeutic effects of domino HT using hepatocytes isolated from explanted human livers for acute liver failure (ALF).
Methods: Isolated hepatocytes were evaluated for viability and function and then transplanted into D-galactosamine/lipopolysaccharide-induced ALF mice via splenic injection. The survival rate was analyzed by the Kaplan-Meier method and log-rank test. Liver function was evaluated by serum biochemical parameters, and inflammatory cytokine levels were measured by ELISA. The pathological changes in the liver tissues were assessed by hematoxylin-eosin staining. Hepatocyte apoptosis was investigated by TUNEL, and hepatocyte apoptosis-related proteins were detected by western blot. The localization of human hepatocytes in the injured mouse livers was detected by immunohistochemical analyses.
Results: Hepatocytes were successfully isolated from explanted livers of 10 pediatric patients with various liver-based metabolic disorders, with an average viability of 85.3% ± 13.0% and average yield of 9.2 × 106 ± 3.4 × 106 cells/g. Isolated hepatocytes had an excellent ability to secret albumin, produce urea, uptake indocyanine green, storage glycogen, and express alpha 1 antitrypsin, albumin, cytokeratin 18, and CYP3A4. Domino HT significantly reduced mortality, decreased serum levels of alanine aminotransferase and aspartate aminotransferase, and improved the pathological damage. Moreover, transplanted hepatocytes inhibited interleukin-6 and tumor necrosis factor-α levels. Domino HT also ameliorates hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells, upregulated Bcl-2, and downregulated Bax expressions. Positive staining for human albumin suggested the localization of human hepatocytes in ALF mice livers.
Conclusion: Explanted livers from patients with inheritable metabolic disorders can serve as a viable cell source for cell-based therapies. Domino HT using hepatocytes with certain metabolic defects has the potential to be a novel therapeutic strategy for ALF.
Keywords: Domino hepatocyte transplantation, Acute liver failure, Inherited metabolic liver disease, Human primary hepatocyte.
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