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https://www.readbyqxmd.com/read/30497023/generation-of-mature-kupffer-cells-from-human-induced-pluripotent-stem-cells
#1
Farah Tasnim, Jiangwa Xing, Xiaozhong Huang, Shupei Mo, Xiaona Wei, Min-Han Tan, Hanry Yu
Liver macrophages, Kupffer cells (KCs), play a critical role in drug-induced liver injury (DILI) and liver diseases including cholestasis, liver fibrosis and viral hepatitis. Application of KCs in in vitro models of DILI and liver diseases is hindered due to limited source of human KCs. In vivo, KCs originate from MYB-independent macrophage progenitors, which differentiate into liver-specific macrophages in response to hepatic cues in the liver. Here, we recapitulated KCs ontogeny by differentiation of MYB-independent iPSCs to macrophage-precursors and exposing them to hepatic cues to generate iPSC-derived KCs (iKCs)...
November 16, 2018: Biomaterials
https://www.readbyqxmd.com/read/30471152/transient-c-src-suppression-during-endodermal-commitment-of-human-ipscs-results-in-abnormal-profibrotic-cholangiocyte-like-cells
#2
Pooja Chaudhari, Lipeng Tian, Amy Kim, Qingfeng Zhu, Robert Anders, Kathleen B Schwarz, Saul Sharkis, Zhaohui Ye, Yoon-Young Jang
Directed differentiation of human induced pluripotent stem cells (iPSCs) toward hepatobiliary lineages has been increasingly used as models of human liver development/diseases. As protein kinases are important components of signaling pathways regulating cell fate changes, we sought to define the key molecular mediators regulating human liver development using inhibitors targeting tyrosine kinases during hepatic differentiation of human iPSCs. A library of tyrosine kinase inhibitors was used for initial screening during the multi-stage differentiation of human iPSCs to hepatic lineage...
November 24, 2018: Stem Cells
https://www.readbyqxmd.com/read/30416049/patient-specific-ipsc-derived-endothelial-cells-provide-long-term-phenotypic-correction-of-hemophilia-a
#3
Cristina Olgasi, Maria Talmon, Simone Merlin, Alessia Cucci, Yvonne Richaud-Patin, Gabriella Ranaldo, Donato Colangelo, Federica Di Scipio, Giovanni N Berta, Chiara Borsotti, Federica Valeri, Francesco Faraldi, Maria Prat, Maria Messina, Piercarla Schinco, Angelo Lombardo, Angel Raya, Antonia Follenzi
We generated patient-specific disease-free induced pluripotent stem cells (iPSCs) from peripheral blood CD34+ cells and differentiated them into functional endothelial cells (ECs) secreting factor VIII (FVIII) for gene and cell therapy approaches to cure hemophilia A (HA), an X-linked bleeding disorder caused by F8 mutations. iPSCs were transduced with a lentiviral vector carrying FVIII transgene driven by an endothelial-specific promoter (VEC) and differentiated into bona fide ECs using an optimized protocol...
November 3, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/30404003/a-screen-using-ipsc-derived-hepatocytes-reveals-nad-as-a-potential-treatment-for-mtdna-depletion-syndrome
#4
Ran Jing, James L Corbett, Jun Cai, Gyda C Beeson, Craig C Beeson, Sherine S Chan, David P Dimmock, Lynn Lazcares, Aron M Geurts, John J Lemasters, Stephen A Duncan
Patients with mtDNA depletion syndrome 3 (MTDPS3) often die as children from liver failure caused by severe reduction in mtDNA content. The identification of treatments has been impeded by an inability to culture and manipulate MTDPS3 primary hepatocytes. Here we generated DGUOK-deficient hepatocyte-like cells using induced pluripotent stem cells (iPSCs) and used them to identify drugs that could improve mitochondrial ATP production and mitochondrial function. Nicotinamide adenine dinucleotide (NAD) was found to improve mitochondrial function in DGUOK-deficient hepatocyte-like cells by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)...
November 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/30358741/biliary-atresia-relevant-human-ipscs-recapitulate-key-disease-features-in-a-dish
#5
Lipeng Tian, Zhaohui Ye, Kim Kafka, Dylan Stewart, Robert Anders, Kathleen B Schwarz, Yoon-Young Jang
Biliary atresia (BA) is the most common cause of pediatric end-stage liver disease and the etiology is poorly understood. There is no effective therapy for BA partly due to lack of human BA models. Towards developing in vitro human models of BA, disease-specific iPSCs from 6 BA patients were generated using non-integrating episomal plasmids. In addition, to determine the functional significance of BA-susceptibility genes identified by genome wide association studies (GWAS) in biliary development, a genome-editing approach was used to create iPSCs with defined mutations in these GWAS BA loci...
October 24, 2018: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/30357207/in-situ-differentiation-and-generation-of-functional-liver-organoids-from-human-ipscs-in-a-3d-perfusable-chip-system
#6
Yaqing Wang, Hui Wang, Pengwei Deng, Wenwen Chen, Yaqiong Guo, Tingting Tao, Jianhua Qin
Liver organoids derived from human pluripotent stem cells (PSCs) represent a new type of in vitro liver model for understanding organ development, disease mechanism and drug testing. However, engineering liver organoids with favorable functions in a controlled cellular microenvironment remains challenging. In this work, we present a new strategy for engineering liver organoids derived from human induced PSCs (hiPSCs) in a 3D perfusable chip system by combining stem cell biology with microengineering technology...
December 7, 2018: Lab on a Chip
https://www.readbyqxmd.com/read/30333205/emerging-models-of-drug-metabolism-transporters-and-toxicity
#7
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
https://www.readbyqxmd.com/read/30317035/human-endogenous-retroviruses-role-in-cancer-cell-stemness
#8
REVIEW
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
https://www.readbyqxmd.com/read/30272645/a-familial-hypercholesterolemia-human-liver-chimeric-mouse-model-using-induced-pluripotent-stem-cell-derived-hepatocytes
#9
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
https://www.readbyqxmd.com/read/30264693/liver-diseases-in-the-dish-ipsc-and-organoids-as-a-new-approach-to-modeling-liver-diseases
#10
REVIEW
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
https://www.readbyqxmd.com/read/30210551/noncoding-rna-transcripts-during-differentiation-of-induced-pluripotent-stem-cells-into-hepatocytes
#11
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
https://www.readbyqxmd.com/read/30166617/publisher-correction-studying-tissue-macrophages-in-vitro-are-ipsc-derived-cells-the-answer
#12
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.
November 2018: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/30149262/human-ips-derived-progenitors-bioengineered-into-liver-organoids-using-an-inverted-colloidal-crystal-poly-ethylene-glycol-scaffold
#13
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
https://www.readbyqxmd.com/read/30143060/biofabrication-of-autologous-human-hepatocytes-for-transplantation-how-do-we-get-there
#14
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
https://www.readbyqxmd.com/read/30130706/investigation-of-the-effect-of-hepatic-metabolism-on-off-target-cardiotoxicity-in-a-multi-organ-human-on-a-chip-system
#15
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
https://www.readbyqxmd.com/read/30102283/semi-automated-production-of-hepatocyte-like-cells-from-pluripotent-stem-cells
#16
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
https://www.readbyqxmd.com/read/30092828/analysis-of-differentially-expressed-genes-among-human-hair-follicle-derived-ipscs-induced-hepatocyte-like-cells-and-primary-hepatocytes
#17
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
https://www.readbyqxmd.com/read/30081348/establishment-and-characterization-of-an-ipsc-line-from-a-58-years-old-high-grade-patient-with-nonalcoholic-fatty-liver-disease-70-steatosis-with-homozygous-wildtype-pnpla3-genotype
#18
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
https://www.readbyqxmd.com/read/30063238/a-glass-based-continuously-zonated-and-vascularized-human-liver-acinus-microphysiological-system-vlamps-designed-for-experimental-modeling-of-diseases-and-adme-tox
#19
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
https://www.readbyqxmd.com/read/30049452/generation-of-hepatic-stellate-cells-from-human-pluripotent-stem-cells-enables-in-vitro-modeling-of-liver-fibrosis
#20
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
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