Cellular and Molecular Gastroenterology and Hepatology

Editor picks for Cellular and Molecular Gastroenterology and Hepatology

Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation We describe a novel porcine 3-dimensional culture model that reproduces esophageal submucosal gland proliferation in vivo associated with cancer and injury.
Oct. 22, 2017

Analysis of Hepatitis C Virus Particle Heterogeneity in Immunodeficient Human Liver Chimeric fah-/- Mice Our work indicates that the heterogeneity in buoyant density of infectious HCV particles evolves over the course of infection and can be influenced by diet.
Oct. 22, 2017

Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells.
Oct. 22, 2017

Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans This study provides the first demonstration of S Typhi–specific responses in the human terminal ileum mucosa .
Oct. 22, 2017

Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis Lamin A/C absence leads to male-selective fatty liver disease and predisposes to nonalcoholic steatohepatitis and fibrosis.
Oct. 22, 2017

Setting up a Lab: The Early Years Dr Habtezion provides advice on successfully navigating the early years of an independent career as a physician-scientist.
Oct. 22, 2017

The Farnesoid X Receptor: Good for BAD Herein, we review current concepts of bile acid diarrhea pathogenesis and the potential role for the farnesoid X receptor in its treatment.
Oct. 22, 2017

Maintaining a Vibrant and Productive Laboratory as a Senior Investigator Dr Boyer discusses his decision to maintain a research program at this stage of his career.
Sept. 1, 2017

Bacterial Autophagy: Offense and Defense at the Host–Pathogen Interface Here we discuss some of these mechanisms, with a special emphasis on the enteric pathogen Salmonella enterica serovar Typhimurium.
Sept. 1, 2017

Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Multiple animal models of clinical pancreatitis have been developed, however, limitations with respect to the pathobiology of human disease make it difficult to assess the validity of animal models.
Sept. 1, 2017

Cellular and Molecular Gastroenterology and Hepatology RSS

  • Pancreas 3D organoids: current and future aspects as a research platform for personalized medicine in pancreatic cancer

    An organoid is as a group of epithelial cells growing in a 3-dimensional structure, with self-renewal and self-organization capacities, which recapitulates the tissue of origin. Use of organoids as a powerful tool for investigation and as a step towards personalized medicine is reviewed.
  • Estrogen receptor alpha loss-of-function protects female mice from DSS-induced experimental colitis

  • Attaching-and-effacing pathogens exploit junction regulatory activities of N-WASP and SNX9 to disrupt the intestinal barrier

    During enteric infection, the attaching-and-effacing pathogen virulence factor EspF targets host N-WASP and SNX9 to promote junctional disruption and intestinal barrier loss. On this basis, the authors propose a novel role for the actin cytoskeletal regulatory protein N-WASP in controlling intestinal epithelial apical junction complex stability.
  • Experimental non-alcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacological activation of Nrf2 (NF-E2-related factor 2)

    In mice with diet-stimulated NASH, pharmacological activation of transcription factor Nrf2 improves glucose homeostasis and inhibits hepatic steatosis, inflammation and fibrosis. Nrf2-mediated amelioration of NASH and liver fibrosis involves downregulation of lipogenic genes, induction of antioxidant genes and suppression of both oxidative and ER stress.
  • Antibiotic treatment leads to fecal Escherichia coli and coliphage expansion in severely malnourished diarrhea patients

    Fecal microbiome of Bangladeshi children treated with antibiotics for severe malnutrition was dominated by Escherichia coli and coliphages. Expansion of E. coli was likely due to the combination of its antibiotic resistance and the ability to utilize host-derived oxidized sugars.
  • Microfabricated Crypt Scaffolds: A New Foundation forEvaluating Human Colon Stem Cells

    The emergence of 3-dimensional organoid technology has significantly advanced the understanding of epithelial stem cell biology within the past decade. Stem cells of the gastrointestinal tract have served as a template for this technology, with initial propagation of mouse intestinal enteroids and colonoids (derived from adult smallintestine or colon crypt units, respectively) and subsequent adaptation of these protocols for human tissue.1-4 As such, researchers may now evaluate basic intestinal and/or colonic stem cell properties directly from patient tissue.
  • Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases

    Enteroid and organoid cultures have revolutionized the study of human small intestinal biology and are outstanding models to explore relationships between microbial organisms and the human host. Increasing the complexity of these cultures will contribute to a better understanding of gut function.
  • Jumonji: Welcome to the World of Interferon Signaling in Alcohol and HCV

    Alcoholic liver disease and hepatitis C virus (HCV) infection, either alone or in combination, affect 2 out of 3 persons living with chronic liver disease in the Western world. Alcohol consumption not only increases the risk of HCV infection, but also works synergistically with HCV to increase hepatotoxicity and the progression to hepatocellular carcinoma (HCC).1 It is known that the increase in hepatotoxicity is caused in part by increased viral replication and impaired innate immune responses.
  • GEMMs Are a Gem When it Comes to Defining the Role of HIF2 in Mucinous Cystic Neoplasms

    The most frequently diagnosed pancreatic malignancy is pancreatic ductal adenocarcinoma (PDA). Invasive PDA constitutes nearly 85% of pancreatic neoplasms, with a strong majority of the patients presenting with distal metastasis at the time of diagnosis, differentiating PDA as one of the most lethal cancers with a 5-year survival rate near 5%. Invasive PDA is dependent on a preceding proliferative and inflammatory pancreatitis event, most frequently pancreatic intraepithelial neoplasms (PanIN) formation with the less frequently observed precursor oncogenic event, mucinous cystic neoplasms (MCN).
  • Cftr Modulates Wnt/-Catenin Signaling and Stem Cell Proliferation in Murine Intestine

    This study documents the functional activity of Cftr in the active intestinal stem cell population of murine intestine. In the absence of Cftr, stem cell proliferation and Wnt/-catenin signaling are increased, which is associated with changes in intracellular pH-dependent plasma membrane localization of the Wnt-transducer Disheveled. Increased stem cell proliferation may contribute to gastrointestinal cancer risk in cystic fibrosis.
  • Bioengineered Liver models for Drug Testing and Cell Differentiation Studies

    This review discusses advances in engineering approaches for constructing liver models with utility in drug screening and for determining microenvironmental determinants of liver cell differentiation/function. Design features and validation of representative models are discussed as well as anticipated future trends.
  • Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter -

    The organic solute transporter - (OST-OST) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OST-OST might have similar beneficial metabolic effects as intestine-specific agonists of major nuclear receptor for bile acids, the farnesoid X receptor (FXR). However, no OST-OST inhibitors have yet been identified.
  • Taming the Wild West of Organoids, Enteroids, and Mini-Guts

    The complex nature of an organ, made up of multiple tissue and cells types, poses an incredible challenge to biologists wishing to interrogate homeostasis or disease. Because of this complexity, it often is difficult to ascertain the cause-and-effect relationship of an experimental manipulation in these systems. For example, in the intestine, a perturbation to the epithelium may elicit an immune response; however, it is difficult to determine if this response is a direct result of the epithelial perturbation, or a consequence of a secondary effect, such as translocation of bacteria across the epithelium.
  • Formation of Giant Lysosome in Neonatal Ileal Enterocytes Requires Endotubin

    Enterocyte maturation involves the development of a highly sophisticated brush border, tight junctions, and an intracellular membrane network pivotal for the intestinal barrier and absorptive functions. Genetic or environmental factors that disrupt the enterocytes proper development can severely impact growth and survival. Interestingly, the developing enterocytes in the ileum of neonates have a transient but distinct morphologic feature: the presence of giant lysosomes in the subapical cytoplasmic region.
  • A Cell Culture Platform to Maintain Long-Term Phenotype ofPrimary Human Hepatocytes and Endothelial Cells

    Modeling interactions between primary human hepatocytes (PHHs) and primary human liver sinusoidal endothelial cells (LSECs) invitro can help elucidate human-specific mechanisms underlying liver physiology/diseaseand drug responses; however, existing hepatocyte/endothelial coculture models are suboptimal because of theiruse of rodent cells, cancerous cell lines, and/or nonliver endothelial cells. Hence, we sought to develop a platform thatcould maintain the long-term phenotype of PHHs and primary human LSECs.
  • Epigenetic Reprogramming of Human Hepatoma Cells: A Low-Cost Option for Drug Metabolism Assessment

    Primary cultures of hepatocytes are widely considered the gold standard for evaluating the hepatic metabolism of pharmacologic molecules.1 However, limited access to human hepatocytes has led to the development of various alternative models.25 The procedures used to generate these cells remain complex and time-consuming. In addition, the resulting hepatocytes frequently display heterogeneous hepatic gene expression, rapidly dedifferentiate, and lose their metabolic functions, which are essential for biological, pharmacologic, and toxicologic studies.
  • Engineered Livers for Infectious Diseases

    Engineered liver systems come in a variety of platform models, from 2-dimensional cocultures of primary humanhepatocytes and stem cellderived progeny, to 3-dimensional organoids and humanized mice. Because of the species-specificity of many human hepatropic pathogens, these engineered systems have been essential tools for biologic discovery and therapeutic agent development in the context of liver-dependent infectious diseases. Although improvement of existing models is always beneficial, and the addition of a robust immune component is a particular need, at present, considerable progress has been made using this combination of research platforms.
  • Endogenous Hydrogen Sulfide Contributes to Tone Generation in Porcine Lower Esophageal Sphincter Via Na+/Ca2+ Exchanger

    Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question.
  • The Endosomal Protein Endotubin Is Required for EnterocyteDifferentiation

    During late embryonic development and through weaning, enterocytes of the ileum are highly endocytic. Defects in endocytosis and trafficking are implicated in neonatal disease, however, the mechanisms regulating trafficking during the developmental period are incompletely understood. The apical endosomal protein endotubin (EDTB) is highly expressed in the late embryonic and neonatal ileum. In epithelial cells invitro, EDTB regulates both trafficking of tight junction proteins and proliferation through modulation of YAP activity.
  • A Molecular Signature of Murine NASH: A Step Closer to a Human Predictive Biomarker?

    Fibrosis is the single best predictor of clinical outcomes in patients with nonalcoholic steatohepatitis (NASH).1,2 Advanced fibrosis portends liver-related mortality and determines the need for liver transplantation.3 Current diagnostic tools assess the presence of hepatic fibrosis but do not predict its development in patients at risk. Risk stratification based on propensity for liver fibrosis is a key factor for the selection of patients who benefit from close follow-up evaluation and medical therapy once approved.
  • Pancreatic HIF2 Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm

    Tissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2 expression in the pancreas have remained undefined.
  • Formation of Human Colonic Crypt Array by Application of Chemical Gradients Across a Shaped Epithelial Monolayer

    The successful culture of intestinal organoids has greatly enhanced our understanding of intestinal stem cell physiology and enabled the generation of novel intestinal disease models. Although of tremendous value, intestinal organoid culture systems have not yet fully recapitulated the anatomy or physiology of the invivo intestinal epithelium. The aim of this work was to re-create an intestinal epithelium with a high density of polarized crypts that respond in a physiologic manner to addition of growth factors, metabolites, or cytokines to the basal or luminal tissue surface as occurs invivo.
  • Indian Hedgehog Suppresses Intestinal Inflammation

    Hedgehog signaling is an evolutionarily conserved pathway that is important for tissue patterning and repair and has been implicated in inflammatory responses for several tissues. However, the gene and cellular targets of the Hedgehog signaling pathway that orchestrate the inflammatory responses are not clearly defined. Hedgehog signaling is mediated by 3 different ligands (sonic hedgehog [Shh], Indian hedgehog [Ihh], and Desert hedgehog [Dhh]), multiple co-receptors (patched, smoothened, growth arrest-specific 1, cell adhesion molecule-related/down-regulated byoncogenes, and brother of cell adhesion molecule-related/down-regulated by oncogenes), 3 transcriptional effectors (glioma [Gli]-associated oncogene homologs 1, 2, 3), and additional regulatory factors.
  • Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and Ethanol Metabolism

    Alcohol-induced progression of hepatitis C virus (HCV) infection is related to dysfunction of innate immunity in hepatocytes. Endogenously produced interferon (IFN) induces activation of interferon-stimulated genes (ISGs) via triggering of the Janus kinasesignal transducer and activator of transcription 1 (STAT1) pathway. This activation requires protein methyltransferase 1regulated arginine methylation of STAT1. Here, we aimed to study whether STAT1 methylation also depended on the levels of demethylase jumonji domain-containing 6 protein (JMJD6) and whether ethanol and HCV affect JMJD6 expression in hepatocytes.
  • Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

    The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis.
  • Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE)

    Eosinophilic esophagitis (EoE) is associated with eosinophil and mast cellaccumulation, which promotes dysphagia and esophageal dysmotility.1,2 Cytokines and chemokines implicated in eosinophil-, mast cell, and basophil-mediated EoE pathogenesis include interleukin (IL)-5, IL-13, thymicstromal lymphopoietin, and eotaxin-3.36 A correlation between IL-5 and eotaxin-3 expression and eosinophil infiltration has been observed.7 Nevertheless, it is not clear if eotaxin-3 is the only chemokine, or one of several, that directs eosinophil accumulation in EoE.
  • Hypoxia in the Gut

    A continuous supply of molecular oxygen is essential for the maintenance of oxidative metabolism and thereby the function and survival of most cells of the human body. Over the course of evolution, we have developed the capacity, at the cellular level, to counteract the threat of developing hypoxia by eliciting an early warning adaptive response that is driven primarily by a transcription factor termed the hypoxia-inducible factor (HIF). In hypoxia, HIF becomes activated and drives the expression of a cohort of genes that promote adaptation to hypoxia including primary regulators of erythropoiesis (eg, erythropoietin), angiogenesis (eg, vascular endothelial growth factor), and metabolism (eg, glycolytic enzymes).
  • Location Matters in Defining T Cellmediated Immunity in Response to Salmonella Typhi Vaccination

    Infection with Salmonella enterica serovar Typhi results in nearly 250,000 deaths and more than 21 million illnesses worldwide. S Typhi is transmitted through the fecal-oral route through contaminated food or water and therefore is a major global health problem in regions that lack the infrastructure to provide safe water and ensure adequate sanitation. Of the 2 widely used S Typhi vaccines, Ty21a is an oral live-attenuated vaccine that confers moderate protection against infection for several years.
  • Lamin Deficiency in the Liver Sets the Stage for Nonalcoholic Steatohepatitis Development in Males

    Nuclear lamins are type V intermediate filament proteins that play important roles in maintaining nuclear shape and in transcriptional regulation. Moreover, they serve as signaling scaffolds at the inner nuclear membrane.1 Nuclear lamins fall into 2 separate classes, A-type and B-type, which are encoded by distinct genes. Mutations in their genes lead to tissue-selective disease phenotypes, termed laminopathies, which can affect muscle, adipose tissue, bone, liver, or multiple tissues depending on the site of the mutation.
  • Heterogeneity of Hepatitis C Virus Particles and Their Evolution During Infection

    Hepatitis C virus (HCV) was identified by molecular cloning of its RNA genome after conventional methods of virus identification failed. This failure was dueto both low levels of HCV particles in the blood of infected patients and particle heterogeneity. HCV is a highly variable virus. In addition to 6 genotypes and more than 60 subtypes, HCV mutants circulate in the blood as millions of quasispecies, many of which are able to escape host immune responses and even direct-acting antiviral (DAA) therapy.
  • Indian Hedgehog Suppresses a Stromal CellDriven Intestinal Immune Response

    Upon intestinal epithelial damage a complex wound healing response is initiated to restore epithelial integrity and defend against pathogenic invasion. Epithelium-derived Indian Hedgehog (Ihh) functions as a critical sensor in this process. Signaling occurs in a paracrine manner because the receptor for Ihh is expressed only in the mesenchyme, but the exact Hedgehog target cell has remained elusive. The aim of this study was to elucidate further the nature of this target cell in the context of intestinal inflammation.
  • Setting up a Lab: The Early Years

    This months Paths and Places column was written by Aida Habtezion, an Associate Professor of Medicine (Gastroenterology and Hepatology) at Stanford University. Dr Habtezion, who studies leukocyte trafficking and the immune response in the gut, provides advice on successfully navigating the early years of an independent career as a physician-scientist. Dr. Habtezion has received multiple awards and was recently promoted to Associate Professor with tenure, making her an ideal role model for early career success.
  • Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans

    Systemic cellular immunity elicited by the Ty21a oral typhoid vaccine has been extensively characterized. However, very limited data are available in humans regarding mucosal immunity at the site of infection (terminal ileum [TI]). Here we investigated the host immunity elicited by Ty21a immunization on terminal ileumlamina propria mononuclear cells (LPMC) and peripheral blood in volunteers undergoing routine colonoscopy.
  • Early Diagnosis of Gastroesophageal Cancers and the Cytosponge: A Work in Progress

    In the Perspective article in the March issue of Cellular and Molecular Gastroenterology and Hepatology,1 the Cytosponge erroneously was cited during the publication process as a Medtronic device (Medtronic, Minneapolis, MN). We would like to clarify that all published studies on Cytosponge to date have been performed using a research design patented by the Medical Research Council UK and made by local manufacturers and performed under permission from the Medical Health Regulatory Agency of the United Kingdom.
  • Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation

    Although cells comprising esophageal submucosal glands (ESMGs) represent a potential progenitor cell niche, new models are needed to understand their capacity to proliferate and differentiate. By histologic appearance, ESMGs have been associated with both overlying normal squamous epithelium and columnar epithelium. Our aim was toassess ESMG proliferation and differentiation in a 3-dimensional culture model.
  • Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication

    The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection.
  • Analysis of Hepatitis C Virus Particle Heterogeneity in Immunodeficient Human Liver Chimeric fah-/- Mice

    Hepatitis C virus (HCV) is a leading cause of chronic liver diseases and the most common indication for liver transplantation in the United States. HCV particles in the blood of infected patients are characterized by heterogeneous buoyant densities, likely owing to HCV association with lipoproteins. However, clinical isolates are not infectious invitro and the relative infectivity of the particles with respect to their buoyant density therefore cannot be determined, pointing to the need for better invivo model systems.
  • Neutrophils as Components of Mucosal Homeostasis

    Inflammatory responses in the intestinal mucosa inevitably result in the recruitment of neutrophils (polymorphonuclear leukocytes [PMNs]). Epithelial cells that line the mucosa play an integral role in the recruitment, maintenance, and clearance of PMNs at sites of inflammation. The consequences of such PMNepithelial interactions often determine tissue responses and, ultimately, organ function. For this reason, there is significant interest in understanding how PMNs function in the mucosa during inflammation.
  • Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis

    Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in LMNA, which encodeslamins A/C, cause laminopathies, including lipodystrophy, cardiomyopathy, and premature aging syndromes. However, the role of lamins in the liver is unknown, and itis unclear whether laminopathy-associated liver disease iscaused by primary hepatocyte defects or systemic alterations.
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