Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis

Coll, Mar; Perea, Luís; Boon, Ruben; Leite, Sofia B.; Vallverdú, Julia; Mannaerts, Inge; Smout, Ayla; Taghdouini, Adil El; Blaya, Delia; Rodrigo-Torres, Daniel; Graupera, Isabel; Aguilar-Bravo, Beatriz; Chesné, Christophe; Najimi, Mustapha; Sokal, Étienne; Lozano, Juan José; Grunsven, Leo A. van; Verfaillie, Catherine M.; Sancho‐Bru, Pau

doi:10.1016/j.stem.2018.05.027

Cited by 194 publications

(236 citation statements)

References 52 publications

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“…Importantly, hPSC‐derived HSCs also expressed lecithin‐retinol acyltransferase ( LRAT ) (Fig. ), an enzyme that plays a key role in the formation of retinyl esters for vitamin A storage . This finding further confirmed that the final progeny are HSCs, which differ from fibroblasts in that the latter do not store vitamin A in lipid droplet.…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 64%

“…HSCs derived by this method express bona fide HSC markers PDGFRA , PDGFRB , CD73 , Desmin ( DES ), and COL1A1 (Fig. ) . Importantly, hPSC‐derived HSCs also expressed lecithin‐retinol acyltransferase ( LRAT ) (Fig.…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 97%

“…Recently HSCs were derived from hPSCs by directed differentiation (Fig. ) . The protocol involves the generation of mesoderm, which is sequentially differentiated into mesenchymal cells, and then mesothelial cells capable of generating HSCs upon exposure to a combination of FGF1 and FGF3, Retinol, and palmitic acid .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

“…) . The protocol involves the generation of mesoderm, which is sequentially differentiated into mesenchymal cells, and then mesothelial cells capable of generating HSCs upon exposure to a combination of FGF1 and FGF3, Retinol, and palmitic acid . HSCs derived by this method express bona fide HSC markers PDGFRA , PDGFRB , CD73 , Desmin ( DES ), and COL1A1 (Fig.…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

“…The combination of hPSC‐derived HSCs with either primary human hepatocytes or the hepatocyte cell line HepaRG, into modular liver organoids results in cell phenotypes that re‐create major features of their in vivo counterparts (Fig. ) . Among those features, the presence of hepatocytes in liver organoids promoted a quiescent phenotype in hPSC‐derived HSCs .…”

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

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Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Sobral-Reyes

Lemos

2019

Stem Cells

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As new applications for human pluripotent stem cell‐derived organoids in drug screenings and tissue replacement therapies emerge, there is a need to examine the mechanisms of tissue injury and repair recently reported for various organoid models. In most cases, organoids contain the main cell types and tissues present in human organs, spatially arranged in a manner that largely resembles the architecture of the organ. Depending on the differentiation protocol used, variations may exist in cell type ratios relative to the organ of reference, and certain tissues, including some parenchymal components and the endothelium, might be poorly represented, or lacking altogether. Despite those caveats, recent studies have shown that organoid tissue injury recapitulates major events and histopathological features of damaged human tissues. In particular, major mechanisms of parenchyma cell damage and interstitial fibrosis can be reproduced with remarkable faithfulness. Although further validation remains to be done in order to establish the relevance of using organoid for either mechanistic studies or drug assays, this technology is becoming a promising tool for the study of human tissue homeostasis, injury, and repair.

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Section: Liver Organoid Damage and Fibrosismentioning

confidence: 64%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 97%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

Section: Liver Organoid Damage and Fibrosismentioning

confidence: 99%

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Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Sobral-Reyes

Lemos

2019

Stem Cells

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The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

Carvalho,

Bansal,

Barrias

et al. 2023

Advanced Materials

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Biomaterials are extensively used to mimic the cell‐matrix interactions, which are essential for cell growth, function and differentiation. This is particularly relevant when developing in vitro disease models of organs rich in extracellular matrix, like the liver. Liver disease involves a chronic wound‐healing response with formation of scar tissue known as liver fibrosis. At early stages, liver disease can be reverted, but as disease progresses, reversion is no longer possible, and there is no cure. Research for new therapies is hampered by the lack of adequate models that replicate the mechanical properties and biochemical stimuli present in the fibrotic liver. Fibrosis is associated with changes in the composition of the extracellular matrix that directly influence cell behavior. Biomaterials could play an essential role in better emulating the disease microenvironment. In this paper, the recent and cutting‐edge biomaterials used for creating in vitro models of human liver fibrosis are revised, in combination with cells, bioprinting and/or microfluidics. These technologies have been instrumental to replicate the intricate structure of the unhealthy tissue and promote medium perfusion that improves cell growth and function, respectively. A comprehensive analysis of the impact of material hints and cell‐material interactions in a 3D context is provided.This article is protected by copyright. All rights reserved

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Comparative Study between the 3D‐Liver Spheroid Models Developed from HepG2 and Immortalized Hepatocyte‐Like Cells with Primary Hepatic Stellate Coculture for Drug Metabolism Analysis and Anticancer Drug Screening

Sae‐be

Wiwatpanit

Varatthan

et al. 2022

Advanced Therapeutics

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Liver spheroids may be the best alternative models for evaluating efficacy and toxicity of the new anticancer candidates and diagnostics for hepatocellular carcinoma (HCC). Here, novel 3D-liver spheroid models are constructed from human hepatoma cells (HepG2)/ immortalized human hepatocyte-like cells (imHCs) with primary hepatic stellate cells (HSCs) coculture using the ultralow attachment technique. Spheroid morphology, HSC distribution, metabolic activity, protein expressions, and drug penetration are evaluated. All developed 3D spheroid models exhibit in spherical shape with narrow size distribution, diameter between 639-743 (HepG2-10%HSC) and 519-631 (imHC-10%HSC) µm. Both imHC mono and coculture models significantly express normal liver biomarkers at the higher level than HepG2 models. While 3D-HepG2 models significantly exhibit HCC biomarkers at the higher level than imHC models. HepG2 and imHC spheroids express basal cytochrom P450 (CYP450) enzymes at different levels depending on cell types, culture period, and ratio of coculture. Their metabolic activities for dextromethorphan (CYP2D6) tolbutamide (CYP2C9) and midazolam (CYP3A4) are routinely evaluated. For midazolam metabolism, imHC models allow the detection of phase II metabolic enzymes (UGT2B4 and UGT2B7). The presence of HSC in HepG2-HSC model increases biological barrier for doxorubicin (DOX) penetration, and escalates IC 50 of DOX from 61.4 to 127.2 µg mL −1 .

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Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis

Cited by 194 publications

References 52 publications

Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

Comparative Study between the 3D‐Liver Spheroid Models Developed from HepG2 and Immortalized Hepatocyte‐Like Cells with Primary Hepatic Stellate Coculture for Drug Metabolism Analysis and Anticancer Drug Screening

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