Advancements in stem cell-derived hepatocyte-like cell models for hepatotoxicity testing

Jin, Mei-Xian; Xiao, Yingying; Liao, Wei; Chen, Qi; Yang, Wenqiang; Yang, Li; Shao, Li; Gao, Yi; Peng, Qing; Zhou, Shuqin

doi:10.1186/s13287-021-02152-9

Cited by 31 publications

(23 citation statements)

References 149 publications

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“…In in vitro models of primary human hepatocytes, immortalized human hepatic cell lines have been used, but they are limited regarding their viability, hepatic gene expression, and function [42]. Of the many options, three-dimensional (3D) models [19][20][21][22][23][24][25][26][27] and stem cell-derived models [43] have also become areas of significant interest. Developing appropriate toxicological model systems is not an easy task, but it will help the effectiveness of toxicological studies.…”

Section: Resultsmentioning

confidence: 99%

The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity

Lőrincz

Deák

Makk-Merczel

et al. 2021

Life

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Investigation of drug-induced liver injuries requires appropriate in vivo and in vitro toxicological model systems. In our study, an attempt was made to compare the hepatocarcinoma HepG2 and the stem cell-derived HepaRG cell lines both in two- and three-dimensional culture conditions to find the most suitable model. Comparison of the liver-specific characteristics of these models was performed via the extent and mechanism of acetaminophen (APAP)-induced hepatotoxicity. Investigating the detailed mechanism of APAP-induced hepatotoxicity, different specific cell death inhibitors were used: the pan-caspase inhibitor zVAD-fmk and dabrafenib significantly protected both cell lines from APAP-induced cell death. However, the known specific inhibitors of necroptosis (necrostatin-1 and MDIVI) were only effective in differentiated HepaRG, which suggest a differential execution of activated pathways in the two models. By applying 3D culture methods, CYP2E1 mRNA levels could be elevated, but we failed to achieve a significant increase in hepatocyte function; hence, the 3D cultivation especially in APAP toxicity studies is not necessarily worth the complicated maintenance. Based on our findings, the hepatocyte functions of HepaRG may stand between the properties of HepG2 cells and primary hepatocytes (PHHs). However, it should be noted that in contrast to PHHs having many limitations, HepaRG cells are relatively immortal, having a stable phenotype and CYP450 expression.

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Section: Resultsmentioning

confidence: 99%

The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity

Lőrincz

Deák

Makk-Merczel

et al. 2021

Life

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“…However, hepatocytes in 2D cultures lack spatial cell‐cell and cell‐matrix interactions, which may affect phenotypic functions. [ 1,2 ] To date, cell‐laden 3D liver constructs have been fabricated as cell microfibers, spheroids, and sheets. [ 3–8 ]…”

Section: Introductionmentioning

confidence: 99%

Production of Multiple Cell‐Laden Microtissue Spheroids with a Biomimetic Hepatic‐Lobule‐Like Structure

Gao

Kim

et al. 2021

Advanced Materials

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The construction of an in vitro 3D cellular model to mimic the human liver is highly desired for drug discovery and clinical applications, such as patient‐specific treatment and cell‐based therapy in regenerative medicine. However, current bioprinting strategies are limited in their ability to generate multiple cell‐laden microtissues with biomimetic structures. This study presents a method for producing hepatic‐lobule‐like microtissue spheroids using a bioprinting system incorporating a precursor cartridge and microfluidic emulsification system. The multiple cell‐laden microtissue spheroids can be successfully generated at a speed of approximately 45 spheroids min−1 and with a uniform diameter. Hepatic and endothelial cells are patterned in a microtissue spheroid with the biomimetic structure of a liver lobule. The spheroids allow long‐term culture with high cell viability, and the structural integrity is maintained longer than that of non‐structured spheroids. Furthermore, structured spheroids show high MRP2, albumin, and CD31 expression levels. In addition, the in vivo study reveals that structured microtissue spheroids are stably engrafted. These results demonstrate that the method provides a valuable 3D structured microtissue spheroid model with lobule‐like constructs and liver functions.

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“…Additionally, recent advances in the bioscience and stem cell field have developed various in vitro models, such as organoids, organ-on designed for reproducing human tissues and organs, being useful in researching novel treatments (Jin et al, 2021;Kulkeaw et al, 2021;Shinozawa et al, 2021). Therapy based on the mesenchymal stem cells (MSCs), is an innovative current method commonly preferred due to their advantages as broad therapeutic potential and easy accessibility.…”

Section: Discussionmentioning

confidence: 99%

Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review

et al. 2022

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Many drugs with different mechanisms of action and indications available on the market today are capable of inducing hepatotoxicity. Drug-induced liver injury (DILI) has been a treatment challenge nowadays as it was in the past. We searched Medline (via PubMed), CENTRAL, Science Citation Index Expanded, clinical trials registries and databases of DILI and hepatotoxicity up to 2021 for novel therapies for the management of adult patients with DILI based on the combination of three main search terms: 1) treatment, 2) novel, and 3) drug-induced liver injury. The mechanism of action of novel therapies, the potential of their benefit in clinical settings, and adverse drug reactions related to novel therapies were extracted. Cochrane Risk of bias tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment approach was involved in the assessment of the certainty of the evidence for primary outcomes of included studies. One thousand three hundred seventy-two articles were identified. Twenty-eight articles were included in the final analysis. Eight randomized controlled trials (RCTs) were detected and for six the available data were sufficient for analysis. In abstract form only we found six studies which were also anaylzed. Investigated agents included: bicyclol, calmangafodipir, cytisin amidophospate, fomepizole, livina-polyherbal preparation, magnesium isoglycyrrhizinate (MgIG), picroliv, plasma exchange, radix Paeoniae Rubra, and S-adenosylmethionine. The primary outcomes of included trials mainly included laboratory markers improvement. Based on the moderate-certainty evidence, more patients treated with MgIG experienced alanine aminotransferase (ALT) normalization compared to placebo. Low-certainty evidence suggests that bicyclol treatment leads to a reduction of ALT levels compared to phosphatidylcholine. For the remaining eight interventions, the certainty of the evidence for primary outcomes was assessed as very low and we are very uncertain in any estimate of effect. More effort should be involved to investigate the novel treatment of DILI. Well-designed RCTs with appropriate sample sizes, comparable groups and precise, not only surrogate outcomes are urgently welcome.

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Advancements in stem cell-derived hepatocyte-like cell models for hepatotoxicity testing

Cited by 31 publications

References 149 publications

The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity

The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity

Production of Multiple Cell‐Laden Microtissue Spheroids with a Biomimetic Hepatic‐Lobule‐Like Structure

Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review

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