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

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

doi:10.7150/thno.26540

Cited by 38 publications

(29 citation statements)

References 34 publications

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“…Ammonia elimination is both a functional marker and a pathogenic molecule. Ammonia elimination correlates with ICP and neuroprotection in our previous large animal studies of SRBAL . Thus, ammonia clearance is a much more reliable marker of hepatocyte function.…”

Section: Discussionmentioning

confidence: 77%

Cold storage of porcine hepatocyte spheroids for spheroid bioartificial liver

Chen

Shaheen

et al. 2019

Xenotransplantation

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Background and aims Cell‐based therapies for liver disease such as bioartificial liver rely on a large quantity and high quality of hepatocytes. Cold storage was previously shown to be a better way to preserve the viability and functionality of hepatocytes during transportation rather than freezing, but this was only proved at a lower density of rat hepatocytes spheroids. The purpose of this study was to optimize conditions for cold storage of high density of primary porcine hepatocyte spheroids. Methods Porcine hepatocytes were isolated by a three‐step perfusion method; hepatocyte spheroids were formed by a 24 hours rocked culture technique. Hepatocyte cell density was 5 × 106/mL in 1000 mL spheroid forming medium. Spheroids were then maintained in rocked culture at 37°C (control condition) or cold stored at 4°C for 24, 48 or 72 hours in four different cold storage solutions: histidine‐tryptophan‐ketoglutarate (HTK) alone; HTK + 1 mM deferoxamine (DEF); HTK + 5 mM N‐acetyl‐L‐cysteine (NAC); and HTK + 1 mM DEF + 5 mM NAC. The viability, ammonia clearance, albumin production, gene expression, and functional activity of cytochrome P450 enzymes were measured after recovery from the cold storage. Results In this study, we observed that cold‐induced injury was reduced by the addition of the iron chelator. Viability of HTK + DEF group hepatocyte spheroids was increased compared with other cold storage groups (P < 0.05). Performance metrics of porcine hepatocyte spheroids cold stored for 24 hours were similar to those in control conditions. The hepatocyte spheroids in control conditions started to lose their ability to clear ammonia while production of albumin was still active at 48 and 72 hours (P < 0.05). In contrast, the viability and functionality of hepatocyte spheroids including ammonia clearance and albumin secretion were preserved in HTK + DEF group at both 48‐ and 72‐hour time points (P < 0.05). Conclusions The beneficial effects of HTK supplemented with DEF were more obvious after cold storage of high density of porcine hepatocyte spheroids for 72 hours. The porcine hepatocyte spheroids were above the cutoff criteria for use in a spheroid‐based bioartificial liver.

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Section: Discussionmentioning

confidence: 77%

Cold storage of porcine hepatocyte spheroids for spheroid bioartificial liver

Chen

Shaheen

et al. 2019

Xenotransplantation

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“…ALB, albumin; CK-18, cytokeratin -18. morbidity and mortality. BAL systems aim to serve as a potential supportive therapy for patients with liver failure that are waiting for or recovering from transplantation (7). However, the development of a BAL has been impeded by the scarcity of suitable biological material (21).…”

Section: Discussionmentioning

confidence: 99%

“…The concept of a bioartificial liver (BAL) has emerged as a potential supportive therapy for patients with liver failure until transplantation can be performed or until recovery is achieved (6). A typical BAL system consists of hepatocytes and either a hollow fiber cartridge or semi-permeable membrane (bioreactor) (7). The efficacy of a BAL system was determined in a clinical study involving 24 patients with fulminant hepatic failure (FHF) (1).…”

Section: Introductionmentioning

confidence: 99%

Human hepatocellular adenoma as a promising cell source for bioartificial liver systems

et al. 2019

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“…In this study, liver organoids were superior in hepatic capacity than umbilical cord-MSC. Bioartificial livers made form porcine liver organoids have reached the nonhuman primate stage [113], demonstrating increased survival for acute liver failure. However, not enough data has been yet generated to be able for comparison with MSC treatment.…”

Section: Future Approaches Using Tissue Engineeringmentioning

confidence: 99%

Mesenchymal Stem Cells for Liver Regeneration in Liver Failure: From Experimental Models to Clinical Trials

Miguel

Prieto

Moratilla

et al. 2019

Stem Cells International

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The liver centralizes the systemic metabolism and thus controls and modulates the functions of the central and peripheral nervous systems, the immune system, and the endocrine system. In addition, the liver intervenes between the splanchnic and systemic venous circulation, determining an abdominal portal circulatory system. The liver displays a powerful regenerative potential that rebuilds the parenchyma after an injury. This regenerative mission is mainly carried out by resident liver cells. However, in many cases this regenerative capacity is insufficient and organ failure occurs. In normal livers, if the size of the liver is at least 30% of the original volume, hepatectomy can be performed safely. In cirrhotic livers, the threshold is 50% based on current practice and available data. Typically, portal vein embolization of the part of the liver that is going to be resected is employed to allow liver regeneration in two-stage liver resection after portal vein occlusion (PVO). However, hepatic resection often cannot be performed due to advanced disease progression or because it is not indicated in patients with cirrhosis. In such cases, liver transplantation is the only treatment possibility, and the need for transplantation is the common outcome of progressive liver disease. It is the only effective treatment and has high survival rates of 83% after the first year. However, donated organs are becoming less available, and mortality and the waiting lists have increased, leading to the initiation of living donor liver transplantations. This type of transplant has overall complications of 38%. In order to improve the treatment of hepatic injury, much research has been devoted to stem cells, in particular mesenchymal stem cells (MSCs), to promote liver regeneration. In this review, we will focus on the advances made using MSCs in animal models, human patients, ongoing clinical trials, and new strategies using 3D organoids.

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

Cited by 38 publications

References 34 publications

Cold storage of porcine hepatocyte spheroids for spheroid bioartificial liver

Cold storage of porcine hepatocyte spheroids for spheroid bioartificial liver

Human hepatocellular adenoma as a promising cell source for bioartificial liver systems

Mesenchymal Stem Cells for Liver Regeneration in Liver Failure: From Experimental Models to Clinical Trials

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