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Ipsc liver

Aarti Sawant-Basak, R Scott Obach
This commentary summarizes expert mini-reviews and original research articles that have been assembled in a special issue on novel models of drug metabolism and disposition. The special issue consists of research articles or reviews on novel static or micro-flow based models of the intestine, liver, eye, and kidney. This issue reviews static intestinal systems like mucosal scrapings and cryopreserved intestinal enterocytes, as well as novel bioengineered or chemically engineered intestinal models derived from primary human tissue, iPSCs, enteroids, and crypts...
November 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Claudia Matteucci, Emanuela Balestrieri, Ayele Argaw-Denboba, Paola Sinibaldi-Vallebona
Cancer incidence and mortality, metastasis, drug resistance and recurrence are still the critical issues of oncological diseases. In this scenario, increasing scientific evidences demonstrate that the activation of human endogenous retroviruses (HERVs) is involved in the aggressiveness of tumors such as melanoma, breast, germ cell, renal, ovarian, liver and haematological cancers. In their dynamic regulation, HERVs have also proved to be important determinants of pluripotency in human embryonic stem cells (ESC) and of the reprogramming process of induced pluripotent stem cells (iPSCs)...
October 11, 2018: Seminars in Cancer Biology
Jiayin Yang, Lai-Yung Wong, Xiao-Yu Tian, Rui Wei, Wing-Hon Lai, Ka-Wing Au, Zhiwei Luo, Carl Ward, Wai-In Ho, David P Ibañez, Hao Liu, Xichen Bao, Baoming Qin, Yu Huang, Miguel A Esteban, Hung-Fat Tse
Familial hypercholesterolemia (FH) is mostly caused by low-density lipoprotein receptor (LDLR) mutations and results in an increased risk of early-onset cardiovascular disease due to marked elevation of LDL cholesterol (LDL-C) in blood. Statins are the first line of lipid-lowering drugs for treating FH and other types of hypercholesterolemia, but new approaches are emerging, in particular PCSK9 antibodies, which are now being tested in clinical trials. To explore novel therapeutic approaches for FH, either new drugs or new formulations, we need appropriate in vivo models...
September 15, 2018: Journal of Visualized Experiments: JoVE
Romina Fiorotto, Mariangela Amenduni, Valeria Mariotti, Luca Fabris, Carlo Spirli, Mario Strazzabosco
Liver diseases negatively impact the quality of life and survival of patients, and often require liver transplantation in cases that progress to organ failure. Understanding the cellular and molecular mechanisms of liver development and pathogenesis has been a challenging task, in part for the lack of adequate cellular models directly relevant to the human diseases. Recent technological advances in the stem cell field have shown the potentiality of induced pluripotent stem cells (iPSC) and liver organoids as the next generation tool to model in vitro liver diseases...
September 5, 2018: Biochimica et biophysica acta. Molecular basis of disease
Aniela Skrzypczyk, Stephanie Kehr, Ilona Krystel, Stephan H Bernhart, Shibashish Giri, Augustinus Bader, Peter F Stadler
Recent advances in the stem cell field allow to obtain many human tissues in vitro. However, hepatic differentiation of induced pluripotent stem cells (iPSCs) still remains challenging. Hepatocyte-like cells (HLCs) obtained after differentiation resemble more fetal liver hepatocytes. MicroRNAs (miRNA) play an important role in the differentiation process. Here, we analysed noncoding RNA profiles from the last stages of differentiation and compare them to hepatocytes. Our results show that HLCs maintain an epithelial character and express miRNA which can block hepatocyte maturation by inhibiting the epithelial-mesenchymal transition (EMT)...
2018: Stem Cells International
Christopher Z W Lee, Tatsuya Kozaki, Florent Ginhoux
In the original Figure 1, an arrow was mistakenly added between the fetal liver monocytes and the short-term and long-term HSCs. This arrow has now been removed.
August 30, 2018: Nature Reviews. Immunology
Soon Seng Ng, Kourosh Saeb-Parsy, Samuel J I Blackford, Joe M Segal, Maria Paola Serra, Marta Horcas-Lopez, Da Yoon No, Sotiris Mastoridis, Wayel Jassem, Curtis W Frank, Nam Joon Cho, Hiromitsu Nakauchi, Jeffrey S Glenn, S Tamir Rashid
Generation of human organoids from induced pluripotent stem cells (iPSCs) offers exciting possibilities for developmental biology, disease modelling and cell therapy. Significant advances towards those goals have been hampered by dependence on animal derived matrices (e.g. Matrigel), immortalized cell lines and resultant structures that are difficult to control or scale. To address these challenges, we aimed to develop a fully defined liver organoid platform using inverted colloid crystal (ICC) whose 3-dimensional mechanical properties could be engineered to recapitulate the extracellular niche sensed by hepatic progenitors during human development...
November 2018: Biomaterials
Nandini Agarwal, Branimir Popovic, Nicole J Martucci, Nicolas A Fraunhoffer, Alejandro Soto-Gutierrez
Directed differentiation of hepatocytes from induced pluripotent stem cells (iPSCs) holds promise as source material for treating some liver disorders. The unlimited availability of perfectly differentiated iPSC-derived hepatocytes will dramatically facilitate cell therapies. While systems to manufacture large quantities of iPSCs-derived cells have been developed, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. This short review highlights important challenges and possible solutions to the current state of hepatocyte biofabrication for cellular therapies to treat liver diseases...
August 24, 2018: Gene Expression
Carlota Oleaga, Anne Riu, Sandra Rothemund, Andrea Lavado, Christopher W McAleer, Christopher J Long, Keisha Persaud, Narasimhan Sriram Narasimhan, My Tran, Jeffry Roles, Carlos A Carmona-Moran, Trevor Sasserath, Daniel H Elbrecht, Lee Kumanchik, L Richard Bridges, Candace Martin, Mark T Schnepper, Gail Ekman, Max Jackson, Ying I Wang, Reine Note, Jessica Langer, Silvia Teissier, James J Hickman
Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function...
November 2018: Biomaterials
Jose Meseguer-Ripolles, Baltasar Lucendo-Villarin, Yu Wang, David C Hay
Human pluripotent stem cells represent a renewable source of human tissue. Our research is focused on generating human liver tissue from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Current differentiation procedures generate human hepatocyte-like cells (HLCs) displaying a mixture of fetal and adult traits. To improve cell phenotype, we have fully defined our differentiation procedure and the cell niche, resulting in the generation of cell populations which display improved gene expression and function...
July 27, 2018: Journal of Visualized Experiments: JoVE
Ziran Xu, Xia He, Xu Shi, Yuhan Xia, Xiaomei Liu, Haitao Wu, Pengdong Li, Hongyu Zhang, Weisi Yin, Xiubo Du, Lisha Li, Yulin Li
BACKGROUND: Differentiation of human induced pluripotent stem cells (hiPSCs) into hepatocytes has important clinical significance in providing a new stem cell source for cell therapy of terminal liver disease. The differential gene expression analysis of hiPSCs, induced hepatocyte-like cells (HLCs), and primary human hepatocytes (PHHs) provides valuable information for optimization of an induction scheme and exploration of differentiation mechanisms. METHODS: Human hair follicle-derived iPSCs (hHF-iPSCs) were induced in vitro by mimicking the environment of a developing liver for 19 days...
August 9, 2018: Stem Cell Research & Therapy
Nina Graffmann, Martina Bohndorf, Audrey Ncube, Wasco Wruck, Karl Kashofer, Kurt Zatloukal, James Adjaye
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and its prevalence increases continuously. Here, we reprogrammed fibroblasts of a high grade NAFLD patient with homozygous wildtype PNPLA3 genotype. We characterized the induced pluripotent stem cells (iPSCs) by immunocytochemistry, flow cytometry, embryoid body formation, pluritest DNA-fingerprinting, and karyotype analysis.
August 2018: Stem Cell Research
Xiang Li, Subin M George, Lawrence Vernetti, Albert H Gough, D Lansing Taylor
The vLAMPS is a human, biomimetic liver MPS, in which the ECM and cell seeding of the intermediate layer prior to assembly, simplifies construction of the model and makes the platform user-friendly. This primarily glass microfluidic device is optimal for real-time imaging, while minimizing the binding of hydrophobic drugs/biologics to the materials that constitute the device. The assembly of the three layered device with primary human hepatocytes and liver sinusoidal endothelial cells (LSECs), and human cell lines for stellate and Kupffer cells, creates a vascular channel separated from the hepatic channel (chamber) by a porous membrane that allows communication between channels, recapitulating the 3D structure of the liver acinus...
August 21, 2018: Lab on a Chip
Mar Coll, Luis Perea, Ruben Boon, Sofia B Leite, Julia Vallverdú, Inge Mannaerts, Ayla Smout, Adil El Taghdouini, Delia Blaya, Daniel Rodrigo-Torres, Isabel Graupera, Beatriz Aguilar-Bravo, Christophe Chesne, Mustapha Najimi, Etienne Sokal, Juan José Lozano, Leo A van Grunsven, Catherine M Verfaillie, Pau Sancho-Bru
The development of complex in vitro hepatic systems and artificial liver devices has been hampered by the lack of reliable sources for relevant cell types, such as hepatic stellate cells (HSCs). Here we report efficient differentiation of human pluripotent stem cells into HSC-like cells (iPSC-HSCs). iPSC-HSCs closely resemble primary human HSCs at the transcriptional, cellular, and functional levels and possess a gene expression profile intermediate between that of quiescent and activated HSCs. Functional analyses revealed that iPSC-HSCs accumulate retinyl esters in lipid droplets and are activated in response to mediators of wound healing, similar to their in vivo counterparts...
July 5, 2018: Cell Stem Cell
Hiroaki Ayabe, Takahisa Anada, Takuo Kamoya, Tomoya Sato, Masaki Kimura, Emi Yoshizawa, Shunyuu Kikuchi, Yasuharu Ueno, Keisuke Sekine, J Gray Camp, Barbara Treutlein, Autumn Ferguson, Osamu Suzuki, Takanori Takebe, Hideki Taniguchi
Timely controlled oxygen (O2 ) delivery is crucial for the developing liver. However, the influence of O2 on intercellular communication during hepatogenesis is unclear. Using a human induced pluripotent stem cell-derived liver bud (hiPSC-LB) model, we found hypoxia induced with an O2 -permeable plate promoted hepatic differentiation accompanied by TGFB1 and TGFB3 suppression. Conversely, extensive hypoxia generated with an O2 -non-permeable plate elevated TGFBs and cholangiocyte marker expression. Single-cell RNA sequencing revealed that TGFB1 and TGFB3 are primarily expressed in the human liver mesenchyme and endothelium similar to in the hiPSC-LBs...
August 14, 2018: Stem Cell Reports
Richard M Giadone, Jessica D Rosarda, Prithvi Reddy Akepati, Arianne C Thomas, Batbold Boldbaatar, Marianne F James, Andrew A Wilson, Vaishali Sanchorawala, Lawreen H Connors, John L Berk, R Luke Wiseman, George J Murphy
Hereditary transthyretin amyloidosis (ATTR amyloidosis) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR amyloidosis, protein secreted from the liver aggregates and forms amyloid fibrils in downstream target organs, chiefly the heart and peripheral nervous system. Few animal models of ATTR amyloidosis exist and none recapitulate the multisystem complexity and clinical variability associated with disease pathogenesis in patients...
July 21, 2018: Amyloid: the International Journal of Experimental and Clinical Investigation
Nina Graffmann, Audrey Ncube, Wasco Wruck, James Adjaye
During embryonic development bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes- the two main cell types within the liver. Cell fate decision depends on elaborate interactions between distinct signalling pathways, namely Notch, WNT, TGFβ, and Hedgehog. Several in vitro protocols have been established to differentiate human pluripotent stem cells into either hepatocyte or cholangiocyte like cells (HLC/CLC) to enable disease modelling or drug screening. During HLC differentiation we observed the occurrence of epithelial cells with a phenotype divergent from the typical hepatic polygonal shape- we refer to these as endoderm derived epithelial cells (EDECs)...
2018: PloS One
Alexander J Kvist, Kajsa P Kanebratt, Anna Walentinsson, Henrik Palmgren, Matthew O'Hara, Anders Björkbom, Linda C Andersson, Marie Ahlqvist, Tommy B Andersson
Primary human hepatocytes (PHH), HepaRG™, HepG2, and two sources of induced pluripotent stem cell (iPSC) derived hepatocytes were characterized regarding gene expression and function of key hepatic proteins, important for the metabolic fate of drugs. The gene expression PCA analysis showed a distance between the two iPSC derived hepatocytes as well as the HepG2 and HepaRG™ cells to the three PHH donors and PHH pool, which were clustered more closely together. Correlation-based hierarchical analysis clustered HepG2 close to the stem cell derived hepatocytes both when the expression of 91 genes related to liver function or only cytochrome P450 (P450) genes were analyzed indicating the non-liver feature and a similar low P450 profile in these cell models...
September 2018: Biochemical Pharmacology
Jui-Tung Liu, Mary Paige Lamprecht, Stephen A Duncan
The ability to differentiate human induced pluripotent stem cells (iPSCs) into hepatocyte-like cells (HLCs) provides new opportunities to study inborn errors in hepatic metabolism. However, to provide a platform that supports the identification of small molecules that can potentially be used to treat liver disease, the procedure requires a culture format that is compatible with screening thousands of compounds. Here, we describe a protocol using completely defined culture conditions, which allow the reproducible differentiation of human iPSCs to hepatocyte-like cells in 96-well tissue culture plates...
May 19, 2018: Journal of Visualized Experiments: JoVE
Y Y Cao, X Zeng
Induced pluripotent stem cells (iPSCs) have the potential of proliferation and differentiation into a variety of somatic cells, including hepatocyte-like cells (HLCs). HLCs from human iPSCs (hiPSC-HLCs) have similar features and functions as primary hepatocytes and are used as an efficient in vitro model of hepatocytes, which brings hope to studies on liver diseases and drug hepatotoxicity evaluation. This article reviews the research advances in hiPSC-HLCs and their application in the fields of disease model, drug hepatotoxicity evaluation, and cell transplantation and discusses the future perspectives of the application of hiPSC-HLCs...
January 20, 2018: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
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