A fully defined matrix to support a pluripotent stem cell derived multi-cell-liver steatohepatitis and fibrosis model

Kumar, Manoj; Toprakhisar, Burak; Haele, Matthias Van; Antoranz, Asier; Boon, Ruben; Chesnais, François; Smedt, Jonathan De; Tricot, Tine; Canella, M.; Tilliole, Pierre; Boeck, Jolan De; Bajaj, Manmohan; Ranga, Adrian; Bosisio, Francesca Maria; Roskams, Tania; Grunsven, Leo A. van; Verfaillie, Cathérine

doi:10.1016/j.biomaterials.2021.121006

Cited by 24 publications

(29 citation statements)

References 52 publications

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“…Based on the expression pattern of mature hepatocyte markers at the RNA and protein level, 3x-AAGLY-HLCs appeared more mature than HepG2 cells but not as mature as HepaRGs and PHHs (Figure 1, Figures S7 and S9). Of note, SBAD2-3x-AAGLY-HLCs displayed lower BFC metabolization than HLC progeny from the 3x-AAGLY-hESC line and two other 3x-AAGLY-hiPSC lines we described previously [15,54]. In addition, these previous studies also demonstrated higher CYP3A4 drug biotransformation by 3x-AAGLY-ESC-derived HLCs than HepaRG cells.…”

Section: Discussionmentioning

confidence: 58%

“…In recent years, advances have been made in the optimization of human-relevant iPSC-derived three-dimensional (3D) spheroid [60][61][62] and organoid [63][64][65] models for long-term toxicological studies, with or without NPCs in co-culture. The Verfaillie lab has also recently described a hydrogel-based 3D co-culture system with improved function and maturation [54]. It will be of interest to differentiate 3x-AAGly-HLCs in combination with iPSC-derived non-parenchymal cells in 3D, for longer term and repeat-dose toxicity studies, and to test its applicability for assessment of toxicity risk and mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity

Ghosh

Smedt

Tricot

et al. 2021

Toxics

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Traditional toxicity risk assessment approaches have until recently focussed mainly on histochemical readouts for cell death. Modern toxicology methods attempt to deduce a mechanistic understanding of pathways involved in the development of toxicity, by using transcriptomics and other big data-driven methods such as high-content screening. Here, we used a recently described optimised method to differentiate human induced pluripotent stem cells (hiPSCs) to hepatocyte-like cells (HLCs), to assess their potential to classify hepatotoxic and non-hepatotoxic chemicals and their use in mechanistic toxicity studies. The iPSC-HLCs could accurately classify chemicals causing acute hepatocellular injury, and the transcriptomics data on treated HLCs obtained by TempO-Seq technology linked the cytotoxicity to cellular stress pathways, including oxidative stress and unfolded protein response (UPR). Induction of these stress pathways in response to amiodarone, diclofenac, and ibuprofen, was demonstrated to be concentration and time dependent. The transcriptomics data on diclofenac-treated HLCs were found to be more sensitive in detecting differentially expressed genes in response to treatment, as compared to existing datasets of other diclofenac-treated in vitro hepatocyte models. Hence iPSC-HLCs generated by transcription factor overexpression and in metabolically optimised medium appear suitable for chemical toxicity detection as well as mechanistic toxicity studies.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity

Ghosh

Smedt

Tricot

et al. 2021

Toxics

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“…Finally, considerable differences in differentiation efficiencies have been observed among different iPSC lines [87], which also needs to be addressed if one wants to efficiently model hepatocyte disorders using patient-derived and isogenic iPSC-HLCs. To enhance fating of HLCs to the level of PHHs, adapted differentiation protocols have included the addition of small molecules that influence different signaling pathways believed to play a role in PHH development, during the differentiation protocol [65,81,82], the use of medium that has optimized nutrient levels [71,83] or a liver-tailored extracellular matrix (ECM) [84]. Alternatively, cell fating can be enhanced by overexpression of hepatic transcription factors (TFs) [71,85] or inclusion of specific miRNAs during differentiation [86].…”

Section: Hepatocytesmentioning

confidence: 99%

Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery

Tricot

Verfaillie

Kumar

2022

Cells

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The pharmaceutical industry is in high need of efficient and relevant in vitro liver models, which can be incorporated in their drug discovery pipelines to identify potential drugs and their toxicity profiles. Current liver models often rely on cancer cell lines or primary cells, which both have major limitations. However, the development of human induced pluripotent stem cells (hiPSCs) has created a new opportunity for liver disease modeling, drug discovery and liver toxicity research. hiPSCs can be differentiated to any cell of interest, which makes them good candidates for disease modeling and drug discovery. Moreover, hiPSCs, unlike primary cells, can be easily genome-edited, allowing the creation of reporter lines or isogenic controls for patient-derived hiPSCs. Unfortunately, even though liver progeny from hiPSCs has characteristics similar to their in vivo counterparts, the differentiation of iPSCs to fully mature progeny remains highly challenging and is a major obstacle for the full exploitation of these models by pharmaceutical industries. In this review, we discuss current liver-cell differentiation protocols and in vitro iPSC-based liver models that could be used for disease modeling and drug discovery. Furthermore, we will discuss the challenges that still need to be overcome to allow for the successful implementation of these models into pharmaceutical drug discovery platforms.

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“…Oleic acid and TGF-β were used to induce the fibrotic and inflammatory phenotype of cells. The given 3D disease model has sustained for a month and has shown peculiar characteristics of the disease model [ 44 ].…”

Section: Development Of Hepatic Tissues: Strategies and Challengesmentioning

confidence: 99%

“…In addition to this, Kumar et al has established a disease model for non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis involving iPSC derived hepatocytes and NPCs. TGF-β and fatty acid were employed to induce inflammatory reactions and fibrosis [ 44 ]. Microfluidic systems with perfusion systems would further enhance the metabolic activity of hepatic organoids.…”

Section: Application Of Hepatic Organoidsmentioning

confidence: 99%

3D Hepatic Organoid-Based Advancements in LIVER Tissue Engineering

2021

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Liver-associated diseases and tissue engineering approaches based on in vitro culture of functional Primary human hepatocytes (PHH) had been restricted by the rapid de-differentiation in 2D culture conditions which restricted their usability. It was proven that cells growing in 3D format can better mimic the in vivo microenvironment, and thus help in maintaining metabolic activity, phenotypic properties, and longevity of the in vitro cultures. Again, the culture method and type of cell population are also recognized as important parameters for functional maintenance of primary hepatocytes. Hepatic organoids formed by self-assembly of hepatic cells are microtissues, and were able to show long-term in vitro maintenance of hepato-specific characteristics. Thus, hepatic organoids were recognized as an effective tool for screening potential cures and modeling liver diseases effectively. The current review summarizes the importance of 3D hepatic organoid culture over other conventional 2D and 3D culture models and its applicability in Liver tissue engineering.

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A fully defined matrix to support a pluripotent stem cell derived multi-cell-liver steatohepatitis and fibrosis model

Cited by 24 publications

References 52 publications

HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity

HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity

Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery

3D Hepatic Organoid-Based Advancements in LIVER Tissue Engineering

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