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Liver / Intestine

Saturday March 25, 2023 - 17:00 to 18:00

Room: Zilker 3-4

115.1 Domino hepatocyte transplantation using explanted human livers with metabolic defects attenuates D-GalN/LPS-induced acute liver failure

Award Winner

Guang-Peng Zhou, People's Republic of China has been granted the TTS Scientific Congress Award

Guang-Peng Zhou, People's Republic of China

Liver Transplantation Center
Beijing Friendship Hospital, Capital Medical University

Biography

Dr. Guang-Peng Zhou is now a clinical postdoctoral fellow and a resident at the Liver Transplantation Center of Beijing Friendship Hospital, Capital Medical University. Since 2015, he has been under the tutelage of Professor Zhi-Jun Zhu, a famous liver transplant surgeon in mainland China, and has participated in over 100 cases of liver transplantation, including living donor liver transplantation and auxiliary liver transplantation. Under the leadership of Professor Zhi-Jun Zhu, their team completed the first case of cross-auxiliary double domino donor liver transplantation in 2013 and the first case of cross-auxiliary domino liver transplantation by exchange of partial liver between two patients with hypermethioninemia and OTCD in 2018. "Liver transplantation without donation" can be achieved by this way. He is currently engaged in clinical and basic research related to liver transplantation and hepatocyte transplantation for the treatment of inherited metabolic liver diseases. He has published several scientific research papers in international journals as the first or co-first author and participated in international conferences including IPTA and ILTS as oral or poster abstract presenter for several times. He obtained “Young Investigator Awards” in 2022 Joint International Congress of ILTS, ELITA, & LICAGE.

Abstract

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.

References:

[1] Zhou GP, Sun LY, Zhu ZJ. The concept of "domino" in liver and hepatocyte transplantation. Therap Adv Gastroenterol. 2020;13:1756284820968755.
[2] Cardoso L, Moreira LFP, Pinto MA, Henriques-Pons A, Alves LA. Domino Hepatocyte Transplantation: A Therapeutic Alternative for the Treatment of Acute Liver Failure. Can J Gastroenterol Hepatol. 2018;2018:2593745.
[3] Dhawan A, Chaijitraruch N, Fitzpatrick E, Bansal S, Filippi C, Lehec SC, Heaton ND, Kane P, Verma A, Hughes RD et al. Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children. J Hepatol. 2020;72:877-84.
[4] Enosawa S, Horikawa R, Yamamoto A, Sakamoto S, Shigeta T, Nosaka S, Fujimoto J, Nakazawa A, Tanoue A, Nakamura K et al. Hepatocyte transplantation using a living donor reduced graft in a baby with ornithine transcarbamylase deficiency: a novel source of hepatocytes. Liver Transpl. 2014;20:391-3.
[5] Stephenne X, Debray FG, Smets F, Jazouli N, Sana G, Tondreau T, Menten R, Goffette P, Boemer F, Schoos R et al. Hepatocyte transplantation using the domino concept in a child with tetrabiopterin nonresponsive phenylketonuria. Cell Transplant. 2012;21:2765-70.
[6] Gramignoli R, Tahan V, Dorko K, Skvorak KJ, Hansel MC, Zhao W, Venkataramanan R, Ellis EC, Jorns C, Ericzon BG et al. New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants. Stem Cell Res. 2013;11:563-73.
[7] Bierwolf J, Lutgehetmann M, Deichmann S, Erbes J, Volz T, Dandri M, Cohen S, Nashan B, Pollok JM. Primary human hepatocytes from metabolic-disordered children recreate highly differentiated liver-tissue-like spheroids on alginate scaffolds. Tissue Eng Part A. 2012;18:1443-53.
[8] Qu W, Wei L, Zhu ZJ, Sun LY, Liu Y, Zeng ZG. Considerations for Use of Domino Cross-auxiliary Liver Transplantation in Metabolic Liver Diseases: A Review of Case Studies. Transplantation. 2019;103:1916-20.

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