Publications by authors named "David Tosh"

91 Publications

Electrochemical Impedance Spectroscopy as a Tool for Monitoring Cell Differentiation from Floor Plate Progenitors to Midbrain Neurons in Real Time.

Adv Biol (Weinh) 2021 Apr 7:e2100330. Epub 2021 Apr 7.

Centre for Biosensors, Bioelectronics and Biodevices (C3Bio), Department of Electronic and Electrical Engineering, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.

Here shows that electrical impedance spectroscopy can be used as a non-invasive and real time tool to probe cell adhesion and differentiation from midbrain floor plate progenitors into midbrain neurons on Au electrodes coated with human laminin. The electrical data and equivalent circuit modeling are consistent with standard microscopy analysis and reveal that within the first 6 hours progenitor cells sediment and attach to the electrode within 40 hours. Between 40 and 120 hours, midbrain progenitor cells differentiate into midbrain neurons, followed by an electrochemically stable maturation phase. The ability to sense and characterize non-invasively and in real time cell differentiation opens up unprecedented avenues for implantable therapies and differentiation strategies.
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http://dx.doi.org/10.1002/adbi.202100330DOI Listing
April 2021

Molecular mechanisms of transcription factor mediated cell reprogramming: conversion of liver to pancreas.

Biochem Soc Trans 2021 Mar 5. Epub 2021 Mar 5.

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, U.K.

Transdifferentiation is a type of cellular reprogramming involving the conversion of one differentiated cell type to another. This remarkable phenomenon holds enormous promise for the field of regenerative medicine. Over the last 20 years techniques used to reprogram cells to alternative identities have advanced dramatically. Cellular identity is determined by the transcriptional profile which comprises the subset of mRNAs, and therefore proteins, being expressed by a cell at a given point in time. A better understanding of the levers governing transcription factor activity benefits our ability to generate therapeutic cell types at will. One well-established example of transdifferentiation is the conversion of hepatocytes to pancreatic β-cells. This cell type conversion potentially represents a novel therapy in T1D treatment. The identification of key master regulator transcription factors (which distinguish one body part from another) during embryonic development has been central in developing transdifferentiation protocols. Pdx1 is one such example of a master regulator. Ectopic expression of vector-delivered transcription factors (particularly the triumvirate of Pdx1, Ngn3 and MafA) induces reprogramming through broad transcriptional remodelling. Increasingly, complimentary cell culture techniques, which recapitulate the developmental microenvironment, are employed to coax cells to adopt new identities by indirectly regulating transcription factor activity via intracellular signalling pathways. Both transcription factor-based reprogramming and directed differentiation approaches ultimately exploit transcription factors to influence cellular identity. Here, we explore the evolution of reprogramming and directed differentiation approaches within the context of hepatocyte to β-cell transdifferentiation focussing on how the introduction of new techniques has improved our ability to generate β-cells.
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http://dx.doi.org/10.1042/BST20200219DOI Listing
March 2021

The Canonical Wnt Pathway as a Key Regulator in Liver Development, Differentiation and Homeostatic Renewal.

Genes (Basel) 2020 Sep 30;11(10). Epub 2020 Sep 30.

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine.
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http://dx.doi.org/10.3390/genes11101163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599793PMC
September 2020

Author Correction: Spatiotemporal regulation of liver development by the Wnt/β-catenin pathway.

Sci Rep 2020 Jul 2;10(1):11169. Epub 2020 Jul 2.

Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-68277-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329859PMC
July 2020

Human Breast Cancer Cells Demonstrate Electrical Excitability.

Front Neurosci 2020 30;14:404. Epub 2020 Apr 30.

Department of Electronic and Electrical Engineering, Centre for Biosensors, Bioelectronics and Biodevices (C3Bio), University of Bath, Bath, United Kingdom.

Breast cancer is one of the most prevalent types of cancers worldwide and yet, its pathophysiology is poorly understood. Single-cell electrophysiological studies have provided evidence that membrane depolarization is implicated in the proliferation and metastasis of breast cancer. However, metastatic breast cancer cells are highly dynamic microscopic systems with complexities beyond a single-cell level. There is an urgent need for electrophysiological studies and technologies capable of decoding the intercellular signaling pathways and networks that control proliferation and metastasis, particularly at a population level. Hence, we present for the first time non-invasive electrical recordings of strongly metastatic MDA-MB-231 and weakly/non-metastatic MCF-7 breast cancer cell lines. To accomplish this, we fabricated an ultra-low noise sensor that exploits large-area electrodes, of 2 mm, which maximizes the double-layer capacitance and concomitant detection sensitivity. We show that the current recorded after adherence of the cells is dominated by the opening of voltage-gated sodium channels (VGSCs), confirmed by application of the highly specific inhibitor, tetrodotoxin (TTX). The electrical activity of MDA-MB-231 cells surpasses that of the MCF-7 cells, suggesting a link between the cells' bioelectricity and invasiveness. We also recorded an activity pattern with characteristics similar to that of Random Telegraph Signal (RTS) noise. RTS patterns were less frequent than the asynchronous VGSC signals. The RTS noise power spectral density showed a Lorentzian shape, which revealed the presence of a low-frequency signal across MDA-MB-231 cell populations with propagation speeds of the same order as those reported for intercellular Ca waves. Our recording platform paves the way for real-time investigations of the bioelectricity of cancer cells, their ionic/pharmacological properties and relationship to metastatic potential.
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http://dx.doi.org/10.3389/fnins.2020.00404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204841PMC
April 2020

Native and invasive squirrels show different behavioural responses to scent of a shared native predator.

R Soc Open Sci 2020 Feb 26;7(2):191841. Epub 2020 Feb 26.

National Museums NI, 153 Bangor Road, Cultra, BT18 0EU Northern Ireland, UK.

Invasive species pose a serious threat to native species. In Europe, invasive grey squirrels () have replaced native red squirrels () in locations across Britain, Ireland and Italy. The European pine marten () can reverse the replacement of red squirrels by grey squirrels, but the underlying mechanism of how pine martens suppress grey squirrels is little understood. Research suggests the reversal process is driven by direct predation, but why the native red squirrel may be less susceptible than the invasive grey squirrel to predation by a commonly shared native predator, is unknown. A behavioural difference may exist with the native sciurid being more effective at avoiding predation by the pine marten with which they have a shared evolutionary history. In mammals, olfactory cues are used by prey species to avoid predators. To test whether anti-predator responses differ between the native red squirrel and the invasive grey squirrel, we exposed both species to scent cues of a shared native predator and quantified the responses of the two squirrel species. Red squirrels responded to pine marten scent by avoiding the feeder, increasing their vigilance and decreasing their feeding activity. By contrast, grey squirrels did not show any anti-predator behaviours in response to the scent of pine marten. Thus, differences in behavioural responses to a shared native predator may assist in explaining differing outcomes of species interactions between native and invasive prey species depending on the presence, abundance and exposure to native predators.
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http://dx.doi.org/10.1098/rsos.191841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062111PMC
February 2020

Seasonal and predator-prey effects on circadian activity of free-ranging mammals revealed by camera traps.

PeerJ 2018 21;6:e5827. Epub 2018 Nov 21.

School of Biological Sciences, Queen's University Belfast, UK.

Endogenous circadian and seasonal activity patterns are adapted to facilitate effective utilisation of environmental resources. Activity patterns are shaped by physiological constraints, evolutionary history, circadian and seasonal changes and may be influenced by other factors, including ecological competition and interspecific interactions. Remote-sensing camera traps allow the collection of species presence data throughout the 24 h period and for almost indefinite lengths of time. Here, we collate data from 10 separate camera trap surveys in order to describe circadian and seasonal activity patterns of 10 mammal species, and, in particular, to evaluate interspecific (dis)associations of five predator-prey pairs. We recorded 8,761 independent detections throughout Northern Ireland. Badgers, foxes, pine martens and wood mice were nocturnal; European and Irish hares and European rabbits were crepuscular; fallow deer and grey and red squirrels were diurnal. All species exhibited significant seasonal variation in activity relative to the timing of sunrise/sunset. Foxes in particular were more crepuscular from spring to autumn and hares more diurnal. Lagged regression analyses of predator-prey activity patterns between foxes and prey (hares, rabbits and wood mice), and pine marten and prey (squirrel and wood mice) revealed significant annual and seasonal cross-correlations. We found synchronised activity patterns between foxes and hares, rabbits and wood mice and pine marten and wood mice, and asynchrony between squirrels and pine martens. Here, we provide fundamental ecological data on endemic, invasive, pest and commercially valuable species in Ireland, as well as those of conservation importance and those that could harbour diseases of economic and/or zoonotic relevance. Our data will be valuable in informing the development of appropriate species-specific methodologies and processes and associated policies.
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http://dx.doi.org/10.7717/peerj.5827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252065PMC
November 2018

Next generation liver model design: Combining a permeable polystyrene membrane with a transdifferentiated cell line.

J Memb Sci 2018 Nov;565:425-438

Department of Chemical Engineering, University of Bath, Bath BA2 7AY, UK.

Herein we describe the manufacture and characterisation of biocompatible, porous polystyrene membranes, suitable for cell culture. Though widely used in traditional cell culture, polystyrene has not been used as a hollow fibre membrane due to its hydrophobicity and non-porous structure. Here, we use microcrystalline sodium chloride (4.7 ± 1.3 µm) to control the porosity of polystyrene membranes and oxygen plasma surface treatment to reduce hydrophobicity. Increased porogen concentration correlates to increased surface pore density, macrovoid formation, gas permeability and mean pore size, but a decrease in mechanical strength. For tissue engineering applications, membranes spun from casting solutions containing 40% (w/w) sodium chloride represent a compromise between strength and permeability, having surface pore density of 208.2 ± 29.7 pores/mm, mean surface pore size of 2.3 ± 0.7 µm, and Young's modulus of 115.0 ± 8.2 MPa. We demonstrate the biocompatibility of the material with an exciting cell line-media combination: transdifferentiation of the AR42J-B13 pancreatic cell line to hepatocyte-like cells. Treatment of AR42J-B13 with dexamethasone/oncostatin-M over 14 days induces transdifferentiation towards a hepatic phenotype. There was a distinct loss of the pancreatic phenotype, shown through loss of expression of the pancreatic marker amylase, and gain of the hepatic phenotype, shown through induction of expression of the hepatic markers transferrin, carbamoylphosphate synthetase and glutamine synthetase. The combination of this membrane fabrication method and demonstration of biocompatibility of the transdifferentiated hepatocytes provides a novel, superior, alternative design for liver models and bioartificial liver devices.
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http://dx.doi.org/10.1016/j.memsci.2018.07.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148409PMC
November 2018

HNF4alpha expression amplifies the glucocorticoid-induced conversion of a human pancreatic cell line to an hepatocyte-like cell.

Biochem Biophys Res Commun 2018 09 26;503(3):1633-1640. Epub 2018 Jul 26.

Institute Cellular Medicine, Health Protection Research Unit, Level 4 Leech, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom. Electronic address:

The pancreas and liver are closely related developmentally and trans-differentiation of cells from one tissue into the cells of the other has been documented to occur after injury or exposure to selected growth factors or glucocorticoid hormones. To generate a readily-expandable source of human hepatocyte-like (H-13) cells, the human pancreatic adenocarcinoma cell (HPAC) line was stably transfected with a construct encoding the variant 2 hepatocyte nuclear factor 4 α (HNF4α) using a piggyBac vector and transient expression of a transposase. Through induction of transgene HNF4α regulated via an upstream glucocorticoid response element in combination with existing modulating effects of glucocorticoid, H-13 cells were converted into quantitatively similar hepatocyte-like (H-13/H) cells based on expression of a variety of hepatocyte proteins. H-13/H cells also demonstrated the ability to store glycogen and lipids. These data provide proof of concept that regulated expression of genes associated with hepatocyte phenotype could be used to generate quantitatively functional human hepatocyte-like cells using a readily expandable cell source and simple culture protocol. This approach would have utility in Toxicology and Hepatology research.
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http://dx.doi.org/10.1016/j.bbrc.2018.07.092DOI Listing
September 2018

Transdifferentiation of pancreatic progenitor cells to hepatocyte-like cells is not serum-dependent when facilitated by extracellular matrix proteins.

Sci Rep 2018 03 12;8(1):4385. Epub 2018 Mar 12.

School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.

The rising prevalence of chronic liver disease, coupled with a permanent shortage of organs for liver transplantation, has sparked enormous interest in alternative treatment strategies. Previous protocols to generate hepatocyte-like cells (HLCs) via pancreas-to-liver transdifferentiation have utilised fetal bovine serum, introducing unknown variables and severely limiting study reproducibility. Therefore, the main goal of this study was to develop a protocol for transdifferentiation of pancreatic progenitor cells to HLCs in a chemically defined, serum-free culture medium. The clonal pancreatic progenitor cell line AR42J-B13 was cultured in basal growth medium on uncoated plastic culture dishes in the absence or presence of Dexamethasone on uncoated, laminin- or fibronectin-coated culture substrata, with or without serum supplementation. The hepatocytic differentiation potential was evaluated: (i) morphologically through bright-field and scanning electron microscopy, (ii) by assessing pancreatic and hepatic marker expression and (iii) by determining the function of HLCs through their ability to synthesise glycogen or take up and release indocyanine green. Here we demonstrate for the first time that transdifferentiation of pancreatic cells to HLCs is not dependent on serum. These results will assist in converting current differentiation protocols into procedures that are compliant with clinical use in future cell-based therapies to treat liver-related metabolic disorders.
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http://dx.doi.org/10.1038/s41598-018-22596-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847606PMC
March 2018

Spatiotemporal regulation of liver development by the Wnt/β-catenin pathway.

Sci Rep 2018 02 9;8(1):2735. Epub 2018 Feb 9.

Centre for Regenerative Medicine, Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

While the Wnt/β-catenin pathway plays a critical role in the maintenance of the zonation of ammonia metabolizing enzymes in the adult liver, the mechanisms responsible for inducing zonation in the embryo are not well understood. Herein we address the spatiotemporal role of the Wnt/β-catenin pathway in the development of zonation in embryonic mouse liver by conditional deletion of Apc and β-catenin at different stages of mouse liver development. In normal development, the ammonia metabolising enzymes carbamoylphosphate synthetase I (CPSI) and Glutamine synthetase (GS) begin to be expressed in separate hepatoblasts from E13.5 and E15.5 respectively and gradually increase in number thereafter. Restriction of GS expression occurs at E18 and becomes increasingly limited to the terminal perivenous hepatocytes postnatally. Expression of nuclear β-catenin coincides with the restriction of GS expression to the terminal perivenous hepatocytes. Conditional loss of Apc resulted in the expression of nuclear β-catenin throughout the developing liver and increased number of cells expressing GS. Conversely, conditional loss of β-catenin resulted in loss of GS expression. These data suggest that the Wnt pathway is critical to the development of zonation as well as maintaining the zonation in the adult liver.
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http://dx.doi.org/10.1038/s41598-018-20888-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807466PMC
February 2018

Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity.

J Med Chem 2017 01 9;60(2):814-820. Epub 2017 Jan 9.

Drug and Target Discovery, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath, Somerset BA2 7AY, U. K.

Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939), i.e., IC = 100 pM vs TNKS2 and IC = 6.5 μM vs PARP1 for 14. In cellular assays, 13 and 14 inhibited Wnt-signaling, enhanced insulin-stimulated glucose uptake, and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 1.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01574DOI Listing
January 2017

Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium.

Differentiation 2017 Jan - Feb;93:39-49. Epub 2016 Nov 19.

Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. Electronic address:

Barrett's metaplasia is the only known morphological precursor to oesophageal adenocarcinoma and is characterized by replacement of stratified squamous epithelium by columnar epithelium. The cell of origin is uncertain and the molecular mechanisms responsible for the change in cellular phenotype are poorly understood. We therefore explored the role of two transcription factors, Cdx2 and HNF4α in the conversion using primary organ cultures. Biopsy samples from cases of human Barrett's metaplasia were analysed for the presence of CDX2 and HNF4α. A new organ culture system for adult murine oesophagus is described. Using this, Cdx2 and HNF4α were ectopically expressed by adenoviral infection. The phenotype following infection was determined by a combination of PCR, immunohistochemical and morphological analyses. We demonstrate the expression of CDX2 and HNF4α in human biopsy samples. Our oesophageal organ culture system expressed markers characteristic of the normal SSQE: p63, K14, K4 and loricrin. Ectopic expression of HNF4α, but not of Cdx2 induced expression of Tff3, villin, K8 and E-cadherin. HNF4α is sufficient to induce a columnar-like phenotype in adult mouse oesophageal epithelium and is present in the human condition. These data suggest that induction of HNF4α is a key early step in the formation of Barrett's metaplasia and are consistent with an origin of Barrett's metaplasia from the oesophageal epithelium.
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http://dx.doi.org/10.1016/j.diff.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293356PMC
August 2017

Maternal vitamin A deficiency during pregnancy affects vascularized islet development.

J Nutr Biochem 2016 10 4;36:51-59. Epub 2016 Aug 4.

Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan. Electronic address:

Vitamin A deficiency is known to affect 20 million pregnant women worldwide. However, the prenatal effects of maternal vitamin A deficiency on pancreas development have not been clearly determined. The present study examined how maternal vitamin A deficiency affects fetal islet development. Vitamin A-deficient mice were generated by feeding female mice with a chemically defined diet lacking vitamin A prior to mating as well as during pregnancy. We found that maternal vitamin A deficiency during pregnancy affected fetal pancreas development. Although the exocrine differentiation appeared normal, development of islet tissue was impaired. In the pancreas of neonatal mice, only a few endocrine cell clusters were formed, and these cell clusters lacked capillary endothelial cells. To further determine how vitamin A metabolites, such as retinoic acid, regulate vascularized islet development, ex vivo culture of embryonic pancreas either in the presence of 4-diethylaminobenzaldehyde (DEAB; an inhibitor of retinaldehyde dehydrogenase), all-trans retinoic acid (atRA) or retinoic acid receptor agonist (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB) was carried out. We found that the addition of DEAB blocked vascularization and suppressed β-cell differentiation. Conversely, atRA or TTNPB promoted β-cell differentiation accompanied by enhanced expression of vascular basement component, laminin. We further demonstrated that atRA regulated vascularization via upregulating vascular endothelial growth factor-A (VEGF-A) secretion in embryonic pancreas and treatment with VEGF-A was able to partially rescue vascularization and β-cell differentiation in DEAB-treated embryonic pancreas cultures. The findings explain why maternal vitamin A deficiency affects fetal islet development and support an essential role of retinoid signaling in regulating vascularized islet development.
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http://dx.doi.org/10.1016/j.jnutbio.2016.07.010DOI Listing
October 2016

Pure species in a continuum of genetic and morphological variation: sympatric oaks at the edge of their range.

Ann Bot 2016 Apr 29;117(4):541-9. Epub 2016 Feb 29.

School of Biological Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK, Quercus, School of Biological Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK and Institute for Global Food Security, Queen's University Belfast

Background And Aims: Studies on oaks (Quercus spp.) have often been hampered by taxonomic confusion, a situation further compounded by the occurrence of extensive interspecific hybridization. In the present study, a combination of genetic and morphological analyses was used to examine sympatric populations of Q. petraea and Q. robur at the north-western edge of their ranges in Northern Ireland, since it had previously been suggested that hybridization could facilitate the apparent rapid, long-distance dispersal of oaks following the glaciations.

Methods: Samples were collected from 24 sites across Northern Ireland that had been previously designated as ancient or semi-natural woodland. Genotypes were obtained from a total of 950 trees using 12 nuclear microsatellite loci, and admixture coefficients were calculated based on a Bayesian clustering approach. Individuals were also classified as Q. petraea,Q. robur or hybrids based on two objective morphometric characters shown previously to delineate pure individuals effectively. Genetically 'pure' individuals of both species, as defined by the Bayesian clustering, were also genotyped for five chloroplast microsatellites.

Key Results: Genetic and morphological analyses both indicated the presence of pure individuals of both species, as well as a continuum of intermediates. There was a good agreement between the molecular and morphological classification, with a generally clear separation between pure individuals.

Conclusions: Despite millennia of hybridization and introgression, genetically and morphologically pure individuals of both Q. petraea and Q. robur can be found at the edge of their range, where both species occur sympatrically. The high proportion of individuals exhibiting introgression compared with previous studies may reflect the historical role of hybridization in facilitating dispersal following the glaciations. This is further supported by the significantly higher chloroplast diversity in Q. robur compared with Q. petraea.
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http://dx.doi.org/10.1093/aob/mcw002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817430PMC
April 2016

MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity.

Toxicol Sci 2015 Mar 18;144(1):173-85. Epub 2014 Dec 18.

MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, UK Stem Cells for Safer Medicines, 7th Floor, Southside, 105 Victoria Street, London SW1E 6QT, UK Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK School of Medicine and Dentistry, University of Central Lancashire, Preston PR1 2HE, UK Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK Endocrinology Department, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9PT, UK Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK, Takara Bio Europe AB (former Cellartis), Arvid Wallgrens Backe 20, 413 46 Göteborg, Sweden, School of Life Sciences, The Systems Biology Research Centre, University of Skövde, Box 408, 541 28 Skövde, Sweden, MRC Centre for Regenerative Medicine, SCRM Building, The University of Edinburgh, Edinburgh Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, UK, Newcastle University, Institute of Cellular Medicine, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK Drug Safety and Metabolism, AstraZeneca R&D, Alderley Park, Cheshire SK10 4TG, UK and North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool L9 7AL, UK MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, UK Stem Cells for Safer Medicines, 7th Floor, Southside, 105 Victoria Street, London SW1E 6QT, UK Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK School of Medicine and Dentistry, University of Central Lancashire, Preston PR1 2HE, UK Centre fo

Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.
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http://dx.doi.org/10.1093/toxsci/kfu269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349141PMC
March 2015

Phosphoinositide 3-kinase alpha-dependent regulation of branching morphogenesis in murine embryonic lung: evidence for a role in determining morphogenic properties of FGF7.

PLoS One 2014 2;9(12):e113555. Epub 2014 Dec 2.

Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.

Branching morphogenesis is a critical step in the development of many epithelial organs. The phosphoinositide-3-kinase (PI3K) pathway has been identified as a central component of this process but the precise role has not been fully established. Herein we sought to determine the role of PI3K in murine lung branching using a series of pharmacological inhibitors directed at this pathway. The pan-class I PI3K inhibitor ZSTK474 greatly enhanced the branching potential of whole murine lung explants as measured by an increase in the number of terminal branches compared with controls over 48 hours. This enhancement of branching was also observed following inhibition of the downstream signalling components of PI3K, Akt and mTOR. Isoform selective inhibitors of PI3K identified that the alpha isoform of PI3K is a key driver in branching morphogenesis. To determine if the effect of PI3K inhibition on branching was specific to the lung epithelium or secondary to an effect on the mesenchyme we assessed the impact of PI3K inhibition in cultures of mesenchyme-free lung epithelium. Isolated lung epithelium cultured with FGF7 formed large cyst-like structures, whereas co-culture with FGF7 and ZSTK474 induced the formation of defined branches with an intact lumen. Together these data suggest a novel role for PI3K in the branching program of the murine embryonic lung contradictory to that reported in other branching organs. Our observations also point towards PI3K acting as a morphogenic switch for FGF7 signalling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113555PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251986PMC
July 2015

In vitro reprogramming of pancreatic alpha cells towards a beta cell phenotype following ectopic HNF4α expression.

Mol Cell Endocrinol 2015 Jan 16;399:50-9. Epub 2014 Sep 16.

Centre for Regenerative Medicine, University of Bath, Bath, UK. Electronic address:

There is currently a shortage of organ donors available for pancreatic beta cell transplantation into diabetic patients. An alternative source of beta cells is pre-existing pancreatic cells. While we know that beta cells can arise directly from alpha cells during pancreatic regeneration we do not understand the molecular basis for the switch in phenotype. The aim of the present study was to investigate if hepatocyte nuclear factor 4 alpha (HNF4α), a transcription factor essential for a normal beta cell phenotype, could induce the reprogramming of alpha cells towards potential beta cells. We utilised an in vitro model of pancreatic alpha cells, the murine αTC1-9 cell line. We initially characterised the αTC1-9 cell line before and following adenovirus-mediated ectopic expression of HNF4α. We analysed the phenotype at transcript and protein level and assessed its glucose-responsiveness. Ectopic HNF4α expression in the αTC1-9 cell line induced a change in morphology (1.7-fold increase in size), suppressed glucagon expression, induced key beta cell-specific markers (insulin, C-peptide, glucokinase, GLUT2 and Pax4) and pancreatic polypeptide (PP) and enabled the cells to secrete insulin in a glucose-regulated manner. In conclusion, HNF4α reprograms alpha cells to beta-like cells.
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http://dx.doi.org/10.1016/j.mce.2014.09.009DOI Listing
January 2015

Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα.

Cell Reprogram 2014 Oct 25;16(5):314-23. Epub 2014 Aug 25.

1 Centre for Regenerative Medicine, Department of Biology & Biochemistry University of Bath , Claverton Down, Bath, BA2 7AY, United Kingdom .

Primary hepatocytes rapidly dedifferentiate when cultured in vitro. We have studied the mechanism of hepatocyte dedifferentiation by using two culture media: one that maintains hepatocytes in a differentiated state and another that allows dedifferentiation. We show that dedifferentiation involves partial transformation of hepatocytes into cells that resemble biliary epithelial cells. Lineage labeling and time-lapse filming confirm that the dedifferentiated cells are derived from hepatocytes and not from contaminating ductal or fibroblastic cells in the original culture. Furthermore, we establish that the conversion of hepatocytes to biliary-like cells is regulated by mutual antagonism of CCAAT/enhancer binding protein alpha (C/EBPα) and SOX9, which have opposing effects on the expression of hepatocyte and ductal genes. Thus, hepatocyte dedifferentiation induces the biliary gene expression program by alleviating C/EBPα-mediated repression of Sox9. We propose that reciprocal antagonism of C/EBPα and SOX9 also operates in the formation of hepatocytes and biliary ducts from hepatoblasts during normal embryonic development. These data demonstrate that reprogramming of differentiated cells can be used to model the acquisition and maintenance of cell fate in vivo.
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http://dx.doi.org/10.1089/cell.2014.0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172464PMC
October 2014

Hollow fibre membrane bioreactors for tissue engineering applications.

Biotechnol Lett 2014 Dec 27;36(12):2357-66. Epub 2014 Jul 27.

Department of Chemical Engineering, Centre for Regenerative Medicine, University of Bath, Bath, BA2 7AY, UK.

Hollow fibre membrane bioreactors (HFB) provide a novel approach towards tissue engineering applications in the field of regenerative medicine. For adherent cell types, HFBs offer an in vivo-like microenvironment as each fibre replicates a blood capillary and the mass transfer rate across the wall is independent from the shear stresses experienced by the cell. HFB also possesses the highest surface area to volume ratio of all bioreactor configurations. In theory, these factors enable a high quantity of the desired cellular product with less population variation, and favourable operating costs. Experimental analyses of different cell types and bioreactor designs show encouraging steps towards producing a clinically relevant device. This review discusses the basic HFB design for cell expansion and in vitro models; compares data produced on commercially available systems and addresses the operational differences between theory and practice. HFBs are showing some potential for mammalian cell culture but further work is needed to fully understand the complexities of cell culture in HFBs and how best to achieve the high theoretical cell yields.
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http://dx.doi.org/10.1007/s10529-014-1619-xDOI Listing
December 2014

Invading and expanding: range dynamics and ecological consequences of the greater white-toothed shrew (Crocidura russula) invasion in Ireland.

PLoS One 2014 23;9(6):e100403. Epub 2014 Jun 23.

School of Biology and Environmental Science, University College Dublin, Dublin, Ireland.

Establishing how invasive species impact upon pre-existing species is a fundamental question in ecology and conservation biology. The greater white-toothed shrew (Crocidura russula) is an invasive species in Ireland that was first recorded in 2007 and which, according to initial data, may be limiting the abundance/distribution of the pygmy shrew (Sorex minutus), previously Ireland's only shrew species. Because of these concerns, we undertook an intensive live-trapping survey (and used other data from live-trapping, sightings and bird of prey pellets/nest inspections collected between 2006 and 2013) to model the distribution and expansion of C. russula in Ireland and its impacts on Ireland's small mammal community. The main distribution range of C. russula was found to be approximately 7,600 km2 in 2013, with established outlier populations suggesting that the species is dispersing with human assistance within the island. The species is expanding rapidly for a small mammal, with a radial expansion rate of 5.5 km/yr overall (2008-2013), and independent estimates from live-trapping in 2012-2013 showing rates of 2.4-14.1 km/yr, 0.5-7.1 km/yr and 0-5.6 km/yr depending on the landscape features present. S. minutus is negatively associated with C. russula. S. minutus is completely absent at sites where C. russula is established and is only present at sites at the edge of and beyond the invasion range of C. russula. The speed of this invasion and the homogenous nature of the Irish landscape may mean that S. minutus has not had sufficient time to adapt to the sudden appearance of C. russula. This may mean the continued decline/disappearance of S. minutus as C. russula spreads throughout the island.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100403PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067332PMC
November 2015

Conversion of one cell type into another: implications for understanding organ development, pathogenesis of cancer and generating cells for therapy.

Biochem Soc Trans 2014 Jun;42(3):609-16

*Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.

Metaplasia is the irreversible conversion of one differentiated cell or tissue type into another. Metaplasia usually occurs in tissues that undergo regeneration, and may, in a pathological context, predispose to an increased risk of disease. Studying the conditions leading to the development of metaplasia is therefore of significant clinical interest. In contrast, transdifferentiation (or cellular reprogramming) is a subset of metaplasia that describes the permanent conversion of one differentiated cell type into another, and generally occurs between cells that arise from neighbouring regions of the same germ layer. Transdifferentiation, although rare, has been shown to occur in Nature. New insights into the signalling pathways involved in normal tissue development may be obtained by investigating the cellular and molecular mechanisms in metaplasia and transdifferentiation, and additional identification of key molecular regulators in transdifferentiation and metaplasia could provide new targets for therapeutic treatment of diseases such as cancer, as well as generating cells for transplantation into patients with degenerative disorders. In the present review, we focus on the transdifferentiation of pancreatic cells into hepatocyte-like cells, the development of Barrett's metaplasia in the oesophagus, and the cellular and molecular mechanisms underlying both processes.
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http://dx.doi.org/10.1042/BST20140058DOI Listing
June 2014

The enone motif of (+)-grandifloracin is not essential for 'anti-austerity' antiproliferative activity.

Bioorg Med Chem Lett 2014 Jul 5;24(13):2815-9. Epub 2014 May 5.

Department of Chemistry, University of Bath, Bath BA2 7AY, United Kingdom. Electronic address:

We report the synthesis and biological evaluation of three analogues of the natural product (+)-grandifloracin (+)-1. All three analogues exhibit enhanced antiproliferative activity against PANC-1 and HT-29 cells compared to the natural product. The retention of activity in an analogue lacking the enone functional group, 9, implies this structural element is not an essential part of the (+)-grandifloracin pharmacophore.
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http://dx.doi.org/10.1016/j.bmcl.2014.04.111DOI Listing
July 2014

Zscan4 is regulated by PI3-kinase and DNA-damaging agents and directly interacts with the transcriptional repressors LSD1 and CtBP2 in mouse embryonic stem cells.

PLoS One 2014 3;9(3):e89821. Epub 2014 Mar 3.

Centre for Regenerative Medicine and Departments of Pharmacy & Pharmacology, University of Bath, Bath, United Kingdom.

The Zscan4 family of genes, encoding SCAN-domain and zinc finger-containing proteins, has been implicated in the control of early mammalian embryogenesis as well as the regulation of pluripotency and maintenance of genome integrity in mouse embryonic stem cells. However, many features of this enigmatic family of genes are poorly understood. Here we show that undifferentiated mouse embryonic stem cell (ESC) lines simultaneously express multiple members of the Zscan4 gene family, with Zscan4c, Zscan4f and Zscan4-ps2 consistently being the most abundant. Despite this, between only 0.1 and 0.7% of undifferentiated mouse pluripotent stem cells express Zscan4 protein at a given time, consistent with a very restricted pattern of Zscan4 transcripts reported previously. Herein we demonstrate that Zscan4 expression is regulated by the p110α catalytic isoform of phosphoinositide 3-kinases and is induced following exposure to a sub-class of DNA-damage-inducing agents, including Zeocin and Cisplatin. Furthermore, we observe that Zscan4 protein expression peaks during the G2 phase of the cell cycle, suggesting that it may play a critical role at this checkpoint. Studies with GAL4-fusion proteins suggest a role for Zscan4 in transcriptional regulation, further supported by the fact that protein interaction analyses demonstrate that Zscan4 interacts with both LSD1 and CtBP2 in ESC nuclei. This study advances and extends our understanding of Zscan4 expression, regulation and mechanism of action. Based on our data we propose that Zscan4 may regulate gene transcription in mouse ES cells through interaction with LSD1 and CtBP2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089821PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940611PMC
January 2015

Squirrelpox virus: assessing prevalence, transmission and environmental degradation.

PLoS One 2014 21;9(2):e89521. Epub 2014 Feb 21.

Quercus, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland.

Red squirrels (Sciurus vulgaris) declined in Great Britain and Ireland during the last century, due to habitat loss and the introduction of grey squirrels (Sciurus carolinensis), which competitively exclude the red squirrel and act as a reservoir for squirrelpox virus (SQPV). The disease is generally fatal to red squirrels and their ecological replacement by grey squirrels is up to 25 times faster where the virus is present. We aimed to determine: (1) the seropositivity and prevalence of SQPV DNA in the invasive and native species at a regional scale; (2) possible SQPV transmission routes; and, (3) virus degradation rates under differing environmental conditions. Grey (n = 208) and red (n = 40) squirrel blood and tissues were sampled. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) techniques established seropositivity and viral DNA presence, respectively. Overall 8% of squirrels sampled (both species combined) had evidence of SQPV DNA in their tissues and 22% were in possession of antibodies. SQPV prevalence in sampled red squirrels was 2.5%. Viral loads were typically low in grey squirrels by comparison to red squirrels. There was a trend for a greater number of positive samples in spring and summer than in winter. Possible transmission routes were identified through the presence of viral DNA in faeces (red squirrels only), urine and ectoparasites (both species). Virus degradation analyses suggested that, after 30 days of exposure to six combinations of environments, there were more intact virus particles in scabs kept in warm (25 °C) and dry conditions than in cooler (5 and 15 °C) or wet conditions. We conclude that SQPV is present at low prevalence in invasive grey squirrel populations with a lower prevalence in native red squirrels. Virus transmission could occur through urine especially during warm dry summer conditions but, more notably, via ectoparasites, which are shared by both species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089521PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931809PMC
October 2014

Barrett's esophagus: cancer and molecular biology.

Ann N Y Acad Sci 2013 Oct;1300:296-314

Department of Medicine, UMDNJ-RWJMS, New Brunswick, New Jersey.

The following paper on the molecular biology of Barrett's esophagus (BE) includes commentaries on signaling pathways central to the development of BE including Hh, NF-κB, and IL-6/STAT3; surgical approaches for esophagectomy and classification of lesions by appropriate therapy; the debate over the merits of minimally invasive esophagectomy versus open surgery; outcomes for patients with pharyngolaryngoesophagectomy; the applications of neoadjuvant chemotherapy and chemoradiotherapy; animal models examining the surgical models of BE and esophageal adenocarcinoma; the roles of various morphogens and Cdx2 in BE; and the use of in vitro BE models for chemoprevention studies.
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http://dx.doi.org/10.1111/nyas.12252DOI Listing
October 2013

Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro: implications for continued therapeutic use.

Eur J Pharm Biopharm 2013 Sep;85(1):12-9

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK; Department of Biology and Biochemistry, University of Bath, Bath, UK.

Cell penetrating peptides (CPPs) offer the exciting potential of effectively delivering macromolecules to the cytoplasm of a cell that are otherwise impermeable to the plasma membrane. Although the use of these peptides has so far been well tolerated in clinical trials, it is important to remember that some of these CPPs were originally derived from pathogenic material. We therefore sought to determine if three of the most widely studied CPPs; HIV-TAT, Antennapedia and Transportan, initiated an immune response in epithelial cells. Using conditions where these peptides efficiently delivered a rhodamine tagged BSA cargo to the interior of epithelial cells, we failed to observe an effect on cell viability as determined by MTT assay (P>0.05). Further, CPP-mediated delivery of this protein cargo failed to activate NFκB, which would be indicative of toll-like receptor signalling. Finally, no significant increase in the release of the inflammatory cytokines interleukin (IL)-8 and IL-6 was detected in epithelial cells exposed to CPP complexes for 72 h (P>0.05). Together, these results indicate that these commonly used CPPs are passive carriers that do not initiate epithelial cell-associated 'danger signals' during the process of cytoplasmic delivery of a model protein cargo.
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http://dx.doi.org/10.1016/j.ejpb.2013.03.024DOI Listing
September 2013

In vitro treatment of carcinoma cell lines with pancreatic (pro)enzymes suppresses the EMT programme and promotes cell differentiation.

Cell Oncol (Dordr) 2013 Jul 16;36(4):289-301. Epub 2013 May 16.

Centre for Regenerative Medicine, Department of Biology & Biochemistry, University of Bath, Bath, UK.

Background: Previous research has suggested a putative utility of pancreatic (pro)enzymes in cancer treatment. The aim of the present study was to investigate the in vitro effects of a mixture of two pancreatic pro-enzymes, i.e., Chymotrypsinogen and Trypsinogen, and the enzyme Amylase on three human cancer cell lines, i.e., OE33 (derived from an oesophageal carcinoma), Panc1 (derived from a pancreatic carcinoma) and Caco-2 (derived from a colon carcinoma).

Results: After treatment of the three cancer cell lines with different doses of the (pro)enzymes for up to 7 days, we observed (i) growth inhibition in a dose-dependent manner, (ii) enhanced expression of β-catenin and E-cadherin and decreased expression of several epithelial-mesenchymal transition (EMT)-associated genes, such as Vimentin, Snail and Slug, (iii) differentiation of Caco-2 cells, including the appearance of cell-specific differentiated structures such as microvilli and tight junctions, the acquisition of a more regular polygonal morphology, and an increased expression of the intestinal differentiation markers alkaline phosphatase and cytokeratin 8, and (iv) differentiation of Panc1 cells, including the formation of cell aggregates, an increment on lamellar bodies and an increased expression of the pancreatic differentiation markers glucagon and insulin.

Conclusions: Our results show that the treatment of three different human cancer cell lines with pancreatic (pro)enzymes results in an enhancement of cell adhesion, an attenuation of several EMT-associated markers, and an increase in the expression of several differentiation-associated markers, suggesting the acquisition of a less malignant phenotype and a decrease in proliferative capacity due to lineage-specific cellular differentiation.
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http://dx.doi.org/10.1007/s13402-013-0134-8DOI Listing
July 2013

Barrett's metaplasia as a paradigm for understanding the development of cancer.

Curr Opin Genet Dev 2012 Oct 11;22(5):494-9. Epub 2012 Sep 11.

Centre for Regenerative Medicine, Department of Biology & Biochemistry, Claverton Down, Bath BA2 7AY, UK.

The conversion of one cell type to another is defined as metaplasia (or sometimes it is referred to as transdifferentiation or cellular reprogramming). Metaplasia is important clinically and may predispose to the development of cancer. Barrett's metaplasia is one such example and is the focus of the present review. Barrett's is a pathological condition in which the normal oesophageal stratified squamous epithelium is replaced by intestinal-type columnar epithelium and is associated with gastro-oesophageal reflux disease. The appearance of columnar epithelium in the oesophagus predisposes to the development of adenocarcinoma. Herein we review the latest evidence on the cellular origin of Barrett's metaplasia. Until recently it was thought that the cellular origin of the columnar epithelium was from a pre-existing cell within the oesophagus. However, recent evidence suggests that this may not be the case. Instead two recent publications indicate that the columnar cells may migrate from a site distal to the oesophagus. These new data contravene our current understanding of metaplasia and raise important questions about the cellular origin of cancer.
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http://dx.doi.org/10.1016/j.gde.2012.08.001DOI Listing
October 2012