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Ipsc liver

Dominic Lenz, Christian Staufner, Selina Wächter, Maike Hagedorn, Juliane Ebersold, Gudrun Göhring, Stefan Kölker, Georg F Hoffmann, Sabine Jung-Klawitter
Fibroblasts of a patient with Infantile Liver Failure Syndrome 2 (OMIM #616483) due to a homozygous missense variant in the neuroblastoma amplified sequence gene (NBAS; c.[2708T>G]; c.[2708T>G]/p.[Leu903Arg]; p.[Leu903Arg]) were reprogrammed to iPSCs using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen) delivering the reprogramming factors Oct3/4, Sox2, c-Myc and Klf4. Cells showed a normal karyotype. Pluripotency of DHMCi004-A was proven using immunohistochemistry, RT-PCR analysis, flow cytometry and differentiation into all three germ layers using the STEMdiff™ Trilineage Differentiation Kit (Stemcell Technologies)...
February 11, 2019: Stem Cell Research
Joseph E Kaserman, Andrew A Wilson
PIZZ alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive disease affecting approximately 100,000 individuals in the United States and one of the most common hereditary causes of liver disease.1 The most common form of the disease results from a single base pair mutation (Glu342Lys), known as the "Z" mutation, that encodes a mutant protein (Z alpha-1 antritypsin [AAT]) that is prone to misfolding and is retained in the endoplasmic reticulum (ER) rather than appropriately secreted. Some of the retained mutant protein attains an unusual aggregated or polymerized conformation...
September 15, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Meng Xiang, Meng Lu, Jing Quan, Ming Xu, Dan Meng, Anfeng Cui, Ning Li, Yingying Liu, Peng Lu, Xueling Kang, Xiaokai Wang, Ning Sun, Meng Zhao, Qiujuan Liang, Lili Le, Xinhong Wang, Jianyi Zhang, Sifeng Chen
Increasing evidence suggests the consensus that direct in vivo application of induced pluripotent stem cells (iPSCs) is infeasible may not be true. Methods: Teratoma formation and fate were examined in 53 normal and disease conditions involving brain, lung, liver, kidney, islet, skin, hind limb, and arteries. Results: Using classic teratoma generation assays, which require iPSCs to be congregated and confined, all mouse, human, and individualized autologous monkey iPSCs tested formed teratoma, while iPSC-derived cells did not...
2019: Theranostics
Suhyun Park, Seon In Hwang, Jonghun Kim, Seoyeon Hwang, Sohee Kang, Sera Yang, Jonghwa Kim, Wonseok Kang, Kyun-Hwan Kim, Dong Wook Han, Yong-Han Paik
BACKGROUND: Until now, there is no effective anti-fibrotic therapy available for liver cirrhosis. Stem cell therapies have been studied for the treatment of hepatic fibrosis. However, the use of embryonic stem cells or induced pluripotent stem cells (iPSC) has limitations such as ethical concern or malignancy potential. Induced hepatocyte-like cells (iHEPs) generated by direct reprogramming technology may overcome these limitations. METHODS: In this study, we generated iHEPs by direct reprogramming from mouse embryonic fibroblast (MEF) either using specific transcription factors such as c-Myc and Klf-4 (type A), or adding small molecules to HNF1α (type B)...
January 11, 2019: Stem Cell Research & Therapy
Fenfang Wu, Di Wu, Yong Ren, Yuhua Huang, Bo Feng, Nan Zhao, Taotao Zhang, Xiaoni Chen, Shangwu Chen, Anlong Xu
BACKGROUND & AIMS: Human induced pluripotent stem cells (iPSC)-derived liver modeling systems have the potential to overcome the shortage of donors for clinical application and become a model for drug development. Although several strategies available to generate hepatic micro-tissues, few have succeeded in generating a liver organoid with hepato-biliary structure from hiPSCs. METHODS: At differentiation stages I and II (day 1-15), 25% of mTeSR culture medium was added to hepatic differentiation medium to induce endodermal and mesodermal commitment and thereafter hepatic and biliary co-differentiation...
January 7, 2019: Journal of Hepatology
Natsuko F Inagaki, Fuyuki F Inagaki, Norihiro Kokudo, Atsushi Miyajima
Mesothelial cells, which cover the surface of visceral organs and serous cavities in mammals, play a crucial role in preventing adhesion. We previously reported that primary mesothelial progenitor cells (MPCs) can not only prevent postoperative adhesion but also promote liver regeneration after hepatectomy. Induced pluripotent stem cells (iPSCs) have the potential to be used for regenerative medicine. Here we have established a differentiation protocol for mouse iPSC-derived MPCs (miMPCs) via the exposure to defined factors, as well as purification using MPC-specific cell surface antigens...
January 4, 2019: FEBS Letters
Carmen Unzu, Evarist Planet, Nathalie Brandenberg, Floriane Fusil, Marco Cassano, Jimena Perez-Vargas, Marc Friedli, François-Loïc Cosset, Matthias P Lutolf, Barbara E Wildhaber, Didier Trono
The liver is an organ with strong regenerative capacity, yet primary hepatocytes have a low amplification potential in vitro, a major limitation for the cell-based therapy of liver disorders and for ex vivo biological screens. Induced pluripotent stem cells (iPSC) may help to circumvent this obstacle, but often harbor genetic and epigenetic abnormalities limiting their potential. Here, we describe the pharmacological induction of proliferative human hepatic progenitor cells (HPC) through a cocktail of growth factors and small molecules mimicking the signaling events involved in liver regeneration...
December 14, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Taketomo Kido, Yuta Koui
Human-induced pluripotent stem cells (iPSCs) could be a useful source for production of hepatocytes. Here, we develop protocols to generate iPSC-derived liver progenitor cells, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs). We also establish long-term two-dimensional co-culture system to induce functional hepatocytes from iPSC-derived liver cells.
2019: Methods in Molecular Biology
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
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
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
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
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 induced pluripotent stem cells (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...
January 2019: Journal of Pediatric Gastroenterology and Nutrition
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
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.
November 2018: Nature Reviews. Immunology
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