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Theranostics. 2018 Nov 9;8(20):5562-5574. doi: 10.7150/thno.26540. eCollection 2018.

Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure.

Li Y1,2,3,4, Wu Q1, Wang Y1,2,3, Weng C5, He Y1, Gao M1, Yang G6, Li L1, Chen F1, Shi Y1, Amiot BP2, Nyberg SL2,3, Bao J1, Bu H1.

Author information

1
Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
2
Department of Surgery, Mayo Clinic, Rochester, MN, USA.
3
William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.
4
Precision Medicine Key Laboratory, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
5
West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan, China.
6
Experimental Animal Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

This study aims to evaluate the effectiveness and safety of the spheroid reservoir bioartificial liver (SRBAL) with porcine hepatocyte organoids in a preclinical nonhuman primate model of acute liver failure (ALF). Methods: Thirty healthy rhesus monkeys were infused with α-amanitin and lipopolysaccharide and randomized into five groups (ALF alone control group; sham no-cell SRBAL treatment group; groups A, B and C with SRBAL treatment started at 12 h, 24 h and 36 h after induction of ALF, respectively). Animals were continuously treated with the SRBAL device for 6 h and followed for up to 336 h. Results: Survival of ALF monkeys improved with hepatocyte SRBAL treatment compared to control groups. Blood ammonia and total bilirubin were lower, and albumin levels were higher in all hepatocyte SRBAL treatment groups. No evidence of porcine endogenous retrovirus was identified in monkey liver or blood after SRBAL treatment. Titers of monkey antibody (IgG, IgM) did not rise after SRBAL treatment. In survival cases, the proportion of necrotic and apoptotic hepatocytes was lower in SRBAL-treated groups, with earlier liver regeneration leading to recovery. Cytokines TNF-α, IL-6, IL-12, IL-1β, IL-8, IFN-γ and IL-2 were ameliorated by the SRBAL treatment, while levels of M-CSF; HGF, EGF and VEGF; IL-1RA and MIF rose on priming, proliferation and the late phase of liver regeneration. Conclusions: The benefit of SRBAL therapy included preventive effects and therapeutic effects. SRBAL improved survival rate and prolonged median survival time in a nonhuman primate model of drug-induced ALF, and these benefits declined with a delay in the initiation of therapy. Improved survival and recovery of ALF monkeys was associated with a reduction in blood ammonia levels, inhibition of the pro-inflammatory response of ALF, and provided a microenvironment more suitable for regeneration of the injured liver.

KEYWORDS:

Macaca mulatta; acute liver failure; bioartificial liver; hepatocyte; organoid

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