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Ipsc liver

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.
July 27, 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...
July 31, 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...
July 12, 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...
June 25, 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
Christian Maass, Matthew Dallas, Matthew E LaBarge, Michael Shockley, Jorge Valdez, Emily Geishecker, Cynthia L Stokes, Linda G Griffith, Murat Cirit
Microphysiological systems (MPS), consisting of tissue constructs, biomaterials, and culture media, aim to recapitulate relevant organ functions in vitro. MPS components are housed in fluidic hardware with operational protocols, such as periodic complete media replacement. Such batch-like operations provide relevant nutrients and remove waste products but also reset cell-secreted mediators (e.g. cytokines, hormones) and potentially limit exposure to drugs (and metabolites). While each component plays an essential role for tissue functionality, MPS-specific nutrient needs are not yet well-characterized nor utilized to operate MPSs at more physiologically-relevant conditions...
May 22, 2018: Scientific Reports
Yueh Chien, Chi-Shuan Huang, Hsin-Chi Lin, Kai-Hsi Lu, Ping-Hsing Tsai, Ying-Hsiu Lai, Kuan-Hsuan Chen, Shou-Dong Lee, Yi-Hsiang Huang, Chien-Ying Wang
The prevalence of nonalcoholic fatty liver disease (NAFLD) is usually increased with age. Non-alcoholic steatohepatitis (NASH), a serious form of NAFLD, may lead to cirrhosis and end-stage liver diseases. Induced pluripotent stem cells (iPSCs) hold promising potential in personalized medicine. Although obviation of c-Myc reduces tumorigenic risk, it also largely reduced the generation of iPSCs. Recently, Poly(ADP-ribose) polymerase 1 (Parp1) has been reported to enhance cell reprogramming. In this study, we demonstrated that forced expression of Oct4/Sox2/Klf4/Parp1 (OSKP) effectively promoted iPSC generation from senescent somatic cells from 18-month-old mouse...
April 6, 2018: Oncotarget
Mousa Kehtari, Bahman Zeynali, Masoud Soleimani, Mahboubeh Kabiri, Ehsan Seyedjafari
Primary hepatocytes, as the gold standard cell type for in vitro models, lose their characteristic morphology and functions after few days. There is an urgent need to develop physiologically relevant models that recapitulate liver microenvironment to obtain mature hepatocyte from stem cells. We designed and fabricated a micro-bioreactor device mimicking the physiological shear stress and cell-cell interaction in liver sinusoid microenvironment. Induced pluripotent stem cells (iPSCs) were co-cultured with human umbilical vein endothelial cells (HUVECs) in the micro-bioreactor device with continuous perfusion of hepatic differentiation medium (100 μL/h)...
April 27, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Monia Cito, Silvia Pellegrini, Lorenzo Piemonti, Valeria Sordi
The experience in the field of islet transplantation shows that it is possible to replace β cells in a patient with type 1 diabetes (T1D), but this cell therapy is limited by the scarcity of organ donors and by the danger associated to the immunosuppressive drugs. Stem cell therapy is becoming a concrete opportunity to treat various diseases. In particular, for a disease like T1D, caused by the loss of a single specific cell type that does not need to be transplanted back in its originating site to perform its function, a stem cell-based cell replacement therapy seems to be the ideal cure...
March 2018: Endocrine Connections
Wasco Wruck, James Adjaye
Induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) differentiated into hepatocyte-like cells (HLCs) provide a defined and renewable source of cells for drug screening, toxicology and regenerative medicine. We previously reprogrammed human fetal foreskin fibroblast cells (HFF1) into iPSCs employing an episomal plasmid-based integration-free approach, this iPSC-line and the hESC lines H1 and H9 were used to model hepatogenesis in vitro. Biochemical characterisation confirmed glycogen storage, ICG uptake and release, urea and bile acid production, as well as CYP3A4 activity...
March 13, 2018: Scientific Data
Sakil Kulkarni, David A Rudnick
Liver-like human cells can be generated from human skin by converting fibroblasts to "induced pluripotent stem cells" (iPSCs), then differentiating the iPSCs into "induced hepatocytes". Although still primarily used as a research tool, emerging applications involving iPSC-derived induced hepatocytes have exciting and provocative clinical and translational potential. This review provides a brief summary of the current status of this field and obstacles that must be overcome before this novel tool will enable precision medicine-based approaches to human liver disease...
May 2018: Journal of Pediatric Gastroenterology and Nutrition
Aline F Ferreira, George A Calin, Virgínia Picanço-Castro, Simone Kashima, Dimas T Covas, Fabiola A de Castro
Although hematopoietic stem cell (HSC) therapy for hematological diseases can lead to a good outcome from the clinical point of view, the limited number of ideal donors, the comorbidity of patients and the increasing number of elderly patients may limit the application of this therapy. HSCs can be generated from induced pluripotent stem cells (iPSCs), which requires the understanding of the bone marrow and liver niches components and function in vivo iPSCs have been extensively applied in several studies involving disease models, drug screening and cellular replacement therapies...
February 21, 2018: Journal of Cell Science
Ran-Ran Zhang, Masaru Koido, Tomomi Tadokoro, Rie Ouchi, Tatsuya Matsuno, Yasuharu Ueno, Keisuke Sekine, Takanori Takebe, Hideki Taniguchi
Early endoderm progenitors naturally possess robust propagating potential to develop a majority of meter-long gastrointestinal tracts and are therefore considered as a promising source for therapy. Here, we demonstrated the reproducible generation of human CDX2+ posterior gut endoderm cells (PGECs) from five induced pluripotent stem cell clones by manipulating FGF, TGF, and WNT signaling. Transcriptome analysis suggested that putative PGECs harbored an intermediate signature profile between definitive endoderm and organ-specific endoderm...
March 13, 2018: Stem Cell Reports
Chelsea Snyder, Lanlan Yu, Tin Ngo, Daniel Sheinson, Yuda Zhu, Min Tseng, Dinah Misner, Karin Staflin
Neurotoxicity is a major concern during drug development, and together with liver and cardio-toxicity, it is one of the main causes of clinical drug attrition. Current pre-clinical models may not sufficiently identify and predict the risk for central or peripheral nervous system toxicity. One such example is clinically dose-limiting neuropathic effects after the administration of chemotherapeutic agents. Thus, the need to establish novel in vitro tools to evaluate the risk of neurotoxicities, such as neuropathy, remains unmet in drug discovery...
August 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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