Assessing Cell Fusion and Cytokinesis Failure as Mechanisms of Clone 9 Hepatocyte Multinucleation In Vitro

Simic, Damir; Euler, Catherine; Thurby, Christina; Peden, Mike; Tannehill-Gregg, Sarah H.; Bunch, Todd; Sanderson, Thomas P.; Vleet, Terry Van

doi:10.1002/0471140856.tx1409s53

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…It consists in the generation of one cell that has two nuclei 20 . Among all the mechanisms that lead to polyploid cells, only two are known to generate binucleated cells: cell fusion and cytokinesis failure 29 .…”

Section: Binucleationmentioning

confidence: 99%

Regulation of cytokinesis and its clinical significance

Tormos¹,

Taléns‐Visconti

Sastre³

2015

Critical Reviews in Clinical Laboratory Sciences

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Dysregulation of the cell cycle leads to polyploid cells, which are classified into mononuclear or binuclear polyploid cells depending on the number of nuclei. Polyploidy is common in plants and in animals. Physiologically, polyploidy and binucleation are differentiation markers and also features of the aging process. In fact, although they provide multiple copies of genes required for survival, a negative correlation between growth capacity and polyploidy has been reported, and thus, suppression or reversal of this phenomenon may be a growth advantage. On the other hand, unscheduled polyploidization may cause genomic instability that might lead to neoplastic aneuploidy. The aim of this review is to analyze the mechanisms that lead to polyploidy, and particularly binucleation, and highlight the potential of ploidy as a marker of illness severity or the success of the adaptive response for an injury, with special emphasis in the liver under physiological and pathological conditions. Hepatocyte binucleation occurs in late fetal development and postnatal maturation, especially after weaning via phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt). It also increases upon aging of the liver as well as in liver cirrhosis and cancer. Liver binucleation mainly indicates the severity of the damage. Furthermore, the eventual increase in hepatocyte binucleation points out compensatory proliferation associated with liver injury. Ploidy conveyor would also permit hepatocyte adaptation to xenobiotic or nutritional injury. In contrast, polyploidy is a feature of many human cancers, and it may predispose to genomic instability and generation of aneuploidization that play a major role in carcinogenesis. Finally, a better understanding of the polyploidization process is needed in order to approach clinical research but also, to get deeper knowledge of cell cycle control. The fascinating regulation of cell cycle in liver and the generation and reversal of ploidies will provide more clues for the mystery of liver regeneration.

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Section: Binucleationmentioning

confidence: 99%

Regulation of cytokinesis and its clinical significance

Tormos¹,

Taléns‐Visconti

Sastre³

2015

Critical Reviews in Clinical Laboratory Sciences

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“…To fully capture the biological complexities involved with toxicity, current in silico models look to integrate existing biological data from in vitro and in vivo bioassays. Toxicogenomic data are often used in early safety assessments to identify mechanisms of preclinical toxicities . More specifically, gene expression data can be used to assess biological responses from drug exposure.…”

Section: Introductionmentioning

confidence: 99%

“…Toxicogenomic data are often used in early safety assessments to identify mechanisms of preclinical toxicities. 23 More specifically, gene expression data can be used to assess biological responses from drug exposure. With the advances in microarray and next-generation sequencing technology, there has been a rapid increase in transcriptomic data in toxicology.…”

Section: Introductionmentioning

confidence: 99%

An Overview of Machine Learning and Big Data for Drug Toxicity Evaluation

Vleet

Gupta

et al. 2019

Chem. Res. Toxicol.

148

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Drug toxicity evaluation is an essential process of drug development as it is reportedly responsible for the attrition of approximately 30% of drug candidates. The rapid increase in the number and types of large toxicology data sets together with the advances in computational methods may be used to improve many steps in drug safety evaluation. The development of in silico models to screen and understand mechanisms of drug toxicity may be particularly beneficial in the early stages of drug development where early toxicity assessment can most reduce expenses and labor time. To facilitate this, machine learning methods have been employed to evaluate drug toxicity but are often limited by small and less diverse data sets. Recent advances in machine learning methods together with the rapid increase in big toxicity data such as molecular descriptors, toxicogenomics, and high-throughput bioactivity data may help alleviate some of the current challenges. In this article, the most common machine learning methods used in toxicity assessment are reviewed together with examples of toxicity studies that have used machine learning methodology. Furthermore, a comprehensive overview of the different types of toxicity tools and data sets available to build in silico toxicity prediction models has been provided to give an overview of the current big toxicity data landscape and highlight opportunities and challenges related to them.

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Cell fusion in the liver, revisited

Lizier

Castelli

Montagna

et al. 2018

WJH

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There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show “transdifferentiation”, but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear.

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Assessing Cell Fusion and Cytokinesis Failure as Mechanisms of Clone 9 Hepatocyte Multinucleation In Vitro

Cited by 3 publications

References 41 publications

Regulation of cytokinesis and its clinical significance

Regulation of cytokinesis and its clinical significance

An Overview of Machine Learning and Big Data for Drug Toxicity Evaluation

Cell fusion in the liver, revisited

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