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

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.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Human Breast Cancer Cells Demonstrate Electrical Excitability.

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.

Correction: Dexamethasone Treatment Induces the Reprogramming of Pancreatic Acinar Cells to Hepatocytes and Ductal Cells.

[This corrects the article DOI: 10.1371/journal.pone.

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

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.

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

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.

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

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.

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

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.

Cellular reprogramming during mouse development.

States of terminal cell differentiation are often considered to be fixed. There are examples, however, in which cells of one type can be converted to a completely different cell type. The process whereby one cell type can be converted to another is referred to as cellular reprogramming.

Ontogenesis of hepatic and pancreatic stem cells.

In the embryo, the liver and pancreas exhibit a close developmental relationship. Both tissues arise from neighbouring regions of the developing endoderm. As well as this close developmental relationship, the liver and pancreas can, under certain circumstances, regenerate functional components.

Molecular aspects of esophageal development.

The following on molecular aspects of esophageal development contains commentaries on esophageal striated myogenesis and transdifferentiation; conversion from columnar into stratified squamous epithelium in the mouse esophagus; the roles for BMP signaling in the developing esophagus and forestomach; and evidence of a direct conversion from columnar to stratified squamous cells in the developing esophagus.

Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells.

Background: The pancreatic exocrine cell line AR42J-B13 can be reprogrammed to hepatocytes following treatment with dexamethasone. The question arises whether dexamethasone also has the capacity to induce ductal cells as well as hepatocytes.

Methodology/principal Findings: AR42J-B13 cells were treated with and without dexamethasone and analyzed for the expression of pancreatic exocrine, hepatocyte and ductal markers.

In vitro reprogramming of pancreatic cells to hepatocytes.

Transdifferentiation is defined as the conversion of one cell type to another. One well-documented example of transdifferentiation is the conversion of pancreatic cells to hepatocytes. Here we describe a robust in vitro model to study pancreas to liver transdifferentiation.

Isolation and culture of embryonic pancreas and liver.

Culturing embryonic tissue in an in vitro setting offers the unique ability to manipulate the external medium and therefore to investigate the pathways involved in regulating normal organogenesis as well as providing models for developmental disorders. Here we describe a system for the in vitro culture of the dorsal pancreatic buds and liver buds from mouse embryos. The tissues are dissected from day 9.

Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.

Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/beta-catenin pathway, we challenged the allele combinations by genetically restricting intracellular beta-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/beta-catenin signaling in the form of an allelic series of mouse mutants.

Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism.

Background And Aims: The Wnt pathway has previously been shown to play a role in hepatic zonation. Herein, we have explored the role of 3 key components (Apc, beta-catenin, and c-Myc) of the Wnt pathway in the zonation of ammonia metabolizing enzymes.

Methods: Conditional deletion of Apc, beta-catenin, and c-Myc was induced in the livers of mice and the expression of periportal and perivenous hepatocyte markers was determined by polymerase chain reaction, Western blotting, and immunohistochemical techniques.

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver.

Dysregulated Wnt signaling is seen in approximately 30% of hepatocellular carcinomas; thus, finding pathways downstream of the activation of Wnt signaling is key. Here, using cre-lox technology, we deleted the Apc gene in the adult mouse liver and observed a rapid increase in nuclear beta-catenin and c-Myc, which is associated with an induction of proliferation that led to hepatomegaly within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes, we analyzed the impact of inactivating APC in the context of deficiency of the potentially key effectors beta-catenin and c-Myc.

Stem cells in the adult pancreas and liver.

Stem cells are undifferentiated cells that can self-renew and generate specialized (functional) cell types. The remarkable ability of stem cells to differentiate towards functional cells makes them suitable modalities in cellular therapy (which means treating diseases with the body's own cells). Potential targets for cellular therapy include diabetes and liver failure.

The Wnt/beta-catenin pathway: master regulator of liver zonation?

The liver contains two systems for the removal of ammonia - the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification.

Liver specification: a new role for Wnts in liver development.

Secreted Wnt proteins control a diverse array of developmental decisions. A recent analysis of the zebrafish mutant prometheus points to a previously unknown role for Wnts during liver specification.

C/EBPalpha and C/EBPbeta are markers of early liver development.

Pancreatic cells can be converted to hepatocytes by overexpression of C/EBPbeta (Shen, C-N, Slack, J.M.W.

The molecular basis of transdifferentiation.

There is now excellent experimental evidence demonstrating the remarkable ability of some differentiated cells to convert to a completely different phenotype. The conversion of one cellular phenotype to another is referred to as 'transdifferentiation' and belongs to a wider class of cell-type switches termed 'metaplasias'. Defining the molecular steps in transdifferentiation will help us to understand the developmental biology of the cells that interconvert, as well as help identify key regulatory transcription factors that may be important for the reprogramming of stem cells.

Characterization of liver function in transdifferentiated hepatocytes.

We previously demonstrated that dexamethasone (Dex) induces the transdifferentiation (or conversion) of the pancreatic progenitor cell line AR42J-B13 (B13) to hepatocytes based on the expression of liver proteins. We have extended our original observations to determine: (1) the effects of Dex on pancreatic gene expression; (2) the time course of expression of liver enriched transcription factors during conversion from pancreatic to hepatic phenotype; (3) the functional potential of transdifferentiated hepatocytes; (4) the proliferative capacity of transdifferentiated hepatocytes; and (5) whether ectopic expression of transcription factors can induce the hepatic phenotype in pancreatic B13 cells. The results were as follows.

Therapeutic potential of transdifferentiated cells.

Cell therapy means treating diseases with the body's own cells. The ability to produce differentiated cell types at will offers a compelling new approach to cell therapy and therefore for the treatment and cure of a plethora of clinical conditions, including diabetes, Parkinson's disease and cardiovascular disease. Until recently, it was thought that differentiated cells could only be produced from embryonic or adult stem cells.