Effects of acute‐liver‐failure‐plasma exposure on hepatic functionality of Hepa<scp>RG</scp>‐<scp>AMC</scp>‐Bioartificial Liver

Nibourg, Geert A. A.; Hoekstra, Ruurdtje; Hoeven, Tessa V. van der; Ackermans, Mariëtte T.; Hakvoort, Theodorus B. M.; Gulik, Thomas M. van; Chamuleau, R. A. F. M.

doi:10.1111/liv.12090

Cited by 15 publications

(13 citation statements)

References 40 publications

(44 reference statements)

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“…ALF plasma contains high levels of hepatotoxic compounds such as cytokines, lipopolysaccharides and biomolecules that are normally detoxified by the liver but due to impaired liver function tend to accumulate in the plasma like ammonia and bile acids28. All these toxins could exert a detrimental effect on the cells used within a BAL device, such as loss of cell-cell contact, cell death due to apoptosis and necrosis, and loss in functionality282930.…”

Section: Resultsmentioning

confidence: 99%

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Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support

Damania

Hassan

Shirakigawa

et al. 2017

Sci Rep

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Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20–60% in the integrated bioreactor as opposed to 5–15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device.

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Section: Resultsmentioning

confidence: 99%

“…All these toxins could exert a detrimental effect on the cells used within a BAL device, such as loss of cell-cell contact, cell death due to apoptosis and necrosis, and loss in functionality282930.…”

Section: Resultsmentioning

confidence: 99%

Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support

Damania

Hassan

Shirakigawa

et al. 2017

Sci Rep

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“…HepaRG cells, a human hepatic bipotent progenitor cell line [102] able to differentiate into hepatocyte clusters and surrounding biliary epithelial-like cells after exposure to dimethyl sulfoxide (DMSO) [103], are now being evaluated for BAL application in the Amsterdam Medical Center (AMC) bioreactor, with mixed results [104,105]. The HepaRG-AMC-BAL has been shown to increase survival time in ALF rats compared to acellular BAL treatment [106].…”

Section: Potential Applications Of Stem Cells In Liver Diseasesmentioning

confidence: 99%

Stem Cell Therapies for Treatment of Liver Disease

et al. 2016

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Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with a focus on the latest studies involving the use of stem cells for the treatment of liver disease. Stem cells can be harvested from a number of sources, or can be generated from somatic cells to create induced pluripotent stem cells (iPSCs). Different cell lines have been used experimentally to support liver function and treat inherited metabolic disorders, acute liver failure, cirrhosis, liver cancer, and small-for-size liver transplantations. Cell-based therapeutics may involve gene therapy, cell transplantation, bioartificial liver devices, or bioengineered organs. Research in this field is still very active. Stem cell therapy may, in the future, be used as a bridge to either liver transplantation or endogenous liver regeneration, but efficient differentiation and production protocols must be developed and safety must be demonstrated before it can be applied to clinical practice.

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“…We determined the effects of h plasma exposure on HepaRG monolayer cultures on total protein content, morphology, ammonia elimination rate, CYP3A4 activity and the transcript levels of the hepatic genes CYP3A4, hepatic nuclear factor 4 Alpha (HNF4A) and arginase 1 (ARG1), which were previously established to be highly responsive to plasma exposure [16,17]. HepaRG monolayers showed a rapid decrease in transcript levels of these hepatic genes when exposed to 100% h plasma (Fig.…”

Section: Healthy-donor Human Plasma Has a Rapid Dose-dependent Detrimentioning

confidence: 99%

“…Currently, the device is loaded with the human liver progenitor cell line HepaRG [14,15], and was proven efficacious in prolonging survival time of rats with ischemic ALF [4]. Previously, we described that healthy-and ALF-rat plasma induced toxicity in HepaRG cells cultured in monolayers and in BALs [16,17].…”

Section: Introductionmentioning

confidence: 99%

HepaRG-Progenitor Cell Derived Hepatocytes Cultured in Bioartificial Livers Are Protected from Healthy- and Acute Liver Failure-Plasma Induced Toxicity

Wenum¹,

Treskes²,

Adam³

et al. 2018

Cell Physiol Biochem

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Background/Aims: For applicability of cell-based therapies aimed at the treatment of liver failure, such as bioartificial livers (BALs) and hepatocyte transplantation, it is essential that the applied hepatocytes tolerate exposure to the patient plasma. However, plasma from both healthy donors and acute liver failure (ALF) patients is detrimental to hepatocytes and hepatic cell lines, such as HepaRG. We aimed to elucidate the underlying mechanisms of plasma-induced toxicity against HepaRG cells in order to ultimately develop methods to reduce this toxicity and render HepaRG-BAL treatment more effective. Methods: Differentiated HepaRG cells cultured in monolayers and laboratory-scale BALs were exposed to culture medium, healthy human plasma, healthy porcine plasma and ALF porcine plasma. Healthy human plasma was fractionated based on size- and polarity, albumin depleted and heat treated to characterize the toxic fraction. The cells were assessed for viability by total protein content and trypan blue staining. Their hepatic differentiation was assessed on transcript level through qRT-PCR and microarray analysis, and on functional level for Cytochrome P450 3A4 activity and ammonia elimination. Mitochondrial damage was assessed by JC-1 staining and mitochondrial gene transcription. Results: Sixteen hours of healthy human plasma exposure did not affect viability, however, hepatic gene-transcript levels decreased dramatically and dose-dependently within four hours of exposure. These changes were associated with early NF-kB signaling and a shift from mitochondrial energy metabolism towards glycolysis. Healthy human plasma-toxicity was associated with the dose-dependent presence of heat-resistant, albumin-bound and (partly) hydrophobic toxic compound(s). HepaRG cells cultured in BALs were partially protected from plasma-toxicity, which was mainly attributable to medium perfusion and/or 3D configuration applied during BAL culturing. The detrimental human plasma effects were reversible in BAL-cultured cells. Porcine ALF-plasma elicited mitotoxicity additional to the basal detrimental effect of porcine healthy plasma, which were only partially reversible. Conclusion: A specific fraction of human plasma reduces hepatic differentiation of HepaRG cultures, in association with early NF-κB activation. In addition, ALF-plasma elicits mitotoxic effects. These findings allow for a targeted approach in preventing plasma-induced cell damage.

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Effects of acute‐liver‐failure‐plasma exposure on hepatic functionality of HepaRG‐AMC‐Bioartificial Liver

Cited by 15 publications

References 40 publications

Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support

Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support

Stem Cell Therapies for Treatment of Liver Disease

HepaRG-Progenitor Cell Derived Hepatocytes Cultured in Bioartificial Livers Are Protected from Healthy- and Acute Liver Failure-Plasma Induced Toxicity

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