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

Yi Li, Qiong Wu, Yujia Wang, Chengxin Weng, Yuting He, Mengyu Gao, Guang Yang, Li Li, Fei Chen, Yujun Shi, Bruce P. Amiot, Scott Nyberg, Ji Bao, Hong Bu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5562-5574
Number of pages13
JournalTheranostics
Volume8
Issue number20
DOIs
StatePublished - Jan 1 2018

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Artificial Liver
Acute Liver Failure
Primates
Liver Regeneration
Haplorhini
Hepatocytes
Ammonia
Swine
Organoids
Amanitins
Endogenous Retroviruses
Control Groups
Macrophage Colony-Stimulating Factor
Therapeutic Uses
Interleukin-12
Macaca mulatta
Interleukin-8
Interleukin-1
Bilirubin
Epidermal Growth Factor

Keywords

  • Acute liver failure
  • Bioartificial liver
  • Hepatocyte
  • Macaca mulatta
  • Organoid

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure. / Li, Yi; Wu, Qiong; Wang, Yujia; Weng, Chengxin; He, Yuting; Gao, Mengyu; Yang, Guang; Li, Li; Chen, Fei; Shi, Yujun; Amiot, Bruce P.; Nyberg, Scott; Bao, Ji; Bu, Hong.

In: Theranostics, Vol. 8, No. 20, 01.01.2018, p. 5562-5574.

Research output: Contribution to journalArticle

Li, Y, Wu, Q, Wang, Y, Weng, C, He, Y, Gao, M, Yang, G, Li, L, Chen, F, Shi, Y, Amiot, BP, Nyberg, S, Bao, J & Bu, H 2018, 'Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure', Theranostics, vol. 8, no. 20, pp. 5562-5574. https://doi.org/10.7150/thno.26540
Li, Yi ; Wu, Qiong ; Wang, Yujia ; Weng, Chengxin ; He, Yuting ; Gao, Mengyu ; Yang, Guang ; Li, Li ; Chen, Fei ; Shi, Yujun ; Amiot, Bruce P. ; Nyberg, Scott ; Bao, Ji ; Bu, Hong. / Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure. In: Theranostics. 2018 ; Vol. 8, No. 20. pp. 5562-5574.
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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.",
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AU - He, Yuting

AU - Gao, Mengyu

AU - Yang, Guang

AU - Li, Li

AU - Chen, Fei

AU - Shi, Yujun

AU - Amiot, Bruce P.

AU - Nyberg, Scott

AU - Bao, Ji

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