Human stem cell-derived encapsulated liver tissue as an effective, consistent and long-lasting in vitro tool for drug testing and development

2017 ◽  
Vol 49 (4) ◽  
pp. e251
Author(s):  
C. Raggi ◽  
M. M’Callum ◽  
C. Mangahas ◽  
Z. Cohen ◽  
A. Shikanov ◽  
...  
Keyword(s):  
Stem Cell ◽  
Liver Tissue ◽  
Drug Testing ◽  
Human Stem Cell

scholarly journals Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions

2021 ◽  
Vol 12 ◽  
Author(s):  
Michelangelo Paci ◽  
Jussi T. Koivumäki ◽  
Hua Rong Lu ◽  
David J. Gallacher ◽  
Elisa Passini ◽  
...  
Keyword(s):  
Experimental Data ◽  
Stem Cell ◽  
In Silico ◽  
Drug Testing ◽  
Drug Application ◽  
Human Stem Cell ◽  
Drug Induced ◽  
Drug Actions ◽  
Experimental Findings

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against in vitro data for 15 drugs.Methods: First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the in silico responses of the three models to drugs, in terms of Ca2+ transient duration (CTD90) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na+ (INa), L-type Ca2+ (ICaL), and rapid delayed rectifying K+ (IKr) currents was quantified. Finally, we compared the drug-induced effects on CTD90 against the corresponding in vitro experiments.Results: The observed CTD90 changes were overall consistent among the in silico models, all three showing changes of smaller magnitudes compared to the ones measured in vitro. For example, sparfloxacin 10 µM induced +42% CTD90 prolongation in vitro, and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) in silico. Different arrhythmic events were observed following drug application, mainly for drugs affecting IKr. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na+ blockers and by drugs with similar effects on ICaL and IKr in Koivumäki2018 and Paci2020, while only by strong ICaL blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis.Conclusion: To conclude, The CTD90 changes observed in silico are qualitatively consistent with our in vitro data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.

scholarly journals A hydrogel platform for in vitro three dimensional assembly of human stem cell-derived islet cells and endothelial cells

2019 ◽  
Vol 97 ◽  
pp. 272-280 ◽  
Author(s):  
Punn Augsornworawat ◽  
Leonardo Velazco-Cruz ◽  
Jiwon Song ◽  
Jeffrey R. Millman
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Islet Cells ◽  
Three Dimensional ◽  
Human Stem Cell

Current Progress in the Creation, Characterization, and Application of Human Stem Cell-derived in Vitro Neuromuscular Junction Models

2021 ◽  
Author(s):  
Eileen Lynch ◽  
Emma Peek ◽  
Megan Reilly ◽  
Claire FitzGibbons ◽  
Samantha Robertson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neuromuscular Junction ◽  
Human Stem Cell ◽  
The Creation

scholarly journals Assessing Drug-Induced Long QT and Proarrhythmic Risk Using Human Stem-Cell-Derived Cardiomyocytes in a Ca2+ Imaging Assay: Evaluation of 28 CiPA Compounds at Three Test Sites

2019 ◽  
Vol 170 (2) ◽  
pp. 345-356 ◽  
Author(s):  
Hua Rong Lu ◽  
Haoyu Zeng ◽  
Ralf Kettenhofen ◽  
Liang Guo ◽  
Ivan Kopljar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Microelectrode Array ◽  
Torsade De Pointes ◽  
Transient Assay ◽  
Potential Drug ◽  
Human Stem Cell ◽  
Long Qt ◽  
Drug Induced ◽  
Vitro Assay

Abstract The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR, and Health and Environmental Sciences Institute (HESI) was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem-cell-derived cardiomyocytes (hSC-CMs). The potential proarrhythmic risks of the 28 comprehensive in vitro proarrhythmia assay (CiPA) drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+-sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of 2 commercially available hSC-CM lines (Cor.4U and CDI iCell Cardiomyocytes) at 3 different test sites. The Ca2+ transient assay, performed at the 3 sites using the 2 different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CiPA drugs and detected cellular arrhythmias-like/early afterdepolarization in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP-risk drugs (54.5%), and 0 of 9 low/no TdP-risk drugs (0%). The results were comparable among the 3 sites and from 2 hSC-CM cell lines. The Ca2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the microelectrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.

scholarly journals Hydrogels for Liver Tissue Engineering

2019 ◽  
Vol 6 (3) ◽  
pp. 59 ◽  
Author(s):  
Shicheng Ye ◽  
Jochem W.B. Boeter ◽  
Louis C. Penning ◽  
Bart Spee ◽  
Kerstin Schneeberger
Keyword(s):  
Tissue Engineering ◽  
Liver Tissue ◽  
Drug Testing ◽  
In Vitro Models ◽  
Liver Tissue Engineering ◽  
Synthetic Materials ◽  
Toxicological Studies ◽  
End Stage

Bioengineered livers are promising in vitro models for drug testing, toxicological studies, and as disease models, and might in the future be an alternative for donor organs to treat end-stage liver diseases. Liver tissue engineering (LTE) aims to construct liver models that are physiologically relevant. To make bioengineered livers, the two most important ingredients are hepatic cells and supportive materials such as hydrogels. In the past decades, dozens of hydrogels have been developed to act as supportive materials, and some have been used for in vitro models and formed functional liver constructs. However, currently none of the used hydrogels are suitable for in vivo transplantation. Here, the histology of the human liver and its relationship with LTE is introduced. After that, significant characteristics of hydrogels are described focusing on LTE. Then, both natural and synthetic materials utilized in hydrogels for LTE are reviewed individually. Finally, a conclusion is drawn on a comparison of the different hydrogels and their characteristics and ideal hydrogels are proposed to promote LTE.

Validation of a novel human stem cell-based gene expression assay for in vitro DART assessment

2019 ◽  
Vol 88 ◽  
pp. 18-19
Author(s):  
Peter I. Racz ◽  
Inger Brandsma ◽  
Sabine Hartvelt ◽  
Tom Zwetsloot ◽  
Giel Hendriks
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Human Stem Cell ◽  
Gene Expression Assay

scholarly journals An In Vitro Model of Latency and Reactivation of Varicella Zoster Virus in Human Stem Cell-Derived Neurons

2015 ◽  
Vol 11 (6) ◽  
pp. e1004885 ◽  
Author(s):  
Amos Markus ◽  
Ilana Lebenthal-Loinger ◽  
In Hong Yang ◽  
Paul R. Kinchington ◽  
Ronald S. Goldstein
Keyword(s):  
Stem Cell ◽  
Varicella Zoster Virus ◽  
In Vitro Model ◽  
Human Stem Cell ◽  
Varicella Zoster ◽  
Vitro Model

scholarly journals In Vitro Differentiated Human Stem Cell-Derived Neurons Reproduce Synaptic Synchronicity Arising during Neurodevelopment

2020 ◽  
Vol 15 (1) ◽  
pp. 22-37 ◽  
Author(s):  
Filip Rosa ◽  
Ashutosh Dhingra ◽  
Betül Uysal ◽  
G. Dulini C. Mendis ◽  
Heidi Loeffler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Human Stem Cell

LIVER TISSUE MODEL FOR DRUG TOXICITY SCREENING

2011 ◽  
Vol 11 (02) ◽  
pp. 369-390 ◽  
Author(s):  
CHUKWUEMEKA ANENE-NZELU ◽  
YAN WANG ◽  
HANRY YU ◽  
LEO HWA LIANG
Keyword(s):  
Liver Tissue ◽  
Drug Testing ◽  
Normal Liver ◽  
3D Models ◽  
New Drugs ◽  
Toxicity Screening ◽  
Cell Sources ◽  
Current Shift ◽  
And Function

Understanding the mechanisms involved in the biotransformation of new drugs and their toxicological implications is important for drug development. In this regard, a lot of effort has been put into research to recreate the liver tissue in the laboratory for the purpose of drug screening. This has also helped to minimize the use of laboratory animal and reduce incidence of post-market withdrawal of drugs. Despite the progress made so far, cell source remains a major limitation since primary human hepatocytes are scarce and the various cell alternatives do not express all the genes found in the normal liver. In terms of tissue construct, there is a current shift to 3D models since the cell–cell interactions found in the 3D configuration enhance the morphology and function of hepatocytes. Furthermore, the engineered tissue's performance can be optimized by cocultures, perfusion-based systems, and the use of scaffolds. Nanotechnology seems promising in the field of tissue engineering, as it has been proven that cell–matrix interactions at the nano level can influence greatly on the outcome of the tissue. The review explores the various cell sources, the 3D model, flow-based systems, cocultures, and nanoscaffolds use in hepatocytes in vitro drug testing

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