SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Gallbladder

149

Gallbladder polyps (GBP) are a common clinical finding that can express malignant potential. The aim of this study was to evaluate whether vegetarianism protects against GBP, together with other putative risk factors.

Concepts: Epidemiology, Cancer, Medical statistics, Gallbladder, Polyp, Vegetarianism, Gallbladder polyp

146

Epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are processes required for embryo organogenesis. Liver develops from the epithelial foregut endoderm from which the liver progenitors, hepatoblasts, are specified. The migrating hepatoblasts acquire a mesenchymal phenotype to form the liver bud. In mid-gestation, hepatoblasts mature into epithelial structures: the hepatocyte cords and biliary ducts. While EMT has been associated with liver bud formation, nothing is known about its contribution to hepatic specification. We previously established an efficient protocol from human embryonic stem cells (hESC) to generate hepatic cells (Hep cells) resembling the hepatoblasts expressing alpha-fetoprotein (AFP) and albumin (ALB). Here we show that Hep cells express both epithelial (EpCAM and E-cadherin) and mesenchymal (vimentin and SNAI-1) markers. Similar epithelial and mesenchymal hepatoblasts were identified in human and mouse fetal livers, suggesting a conserved interspecies phenotype. Knock-down experiments demonstrated the importance of SNAI-1 in Hep cell hepatic specification. Moreover, ChIP assays revealed direct binding of SNAI-1 in the promoters of AFP and ALB genes consistent with its transcriptional activator function in hepatic specification. Altogether, our hESC-derived Hep cell cultures reveal the dual mesenchymal and epithelial phenotype of hepatoblast-like cells and support the unexpected transcriptional activator role of SNAI-1 in hepatic specification.

Concepts: Gene, Gene expression, Transcription, Stem cell, Liver, Transcription factor, Embryonic stem cell, Gallbladder

139

Cholangiocarcinoma (CCA) is an aggressive cancer arising from epithelial cells of the bile duct. Most patients with CCA have an unresectable tumor at the time of diagnosis. In Western countries, the risk of CCA increases in patients with primary sclerosing cholangitis, whereas liver fluke infection appears to be the major risk factor for CCA in Asian countries. A diagnosis of liver fluke infection often relies on stool samples, including microscopic examination, polymerase chain reaction-based assays, and fluke antigen detection. Tests of serum, saliva and urine samples are also potentially diagnostic. The presence of liver fluke along with exogenous carcinogens magnifies the risk of CCA in people living in endemic areas. The “liver fluke-cholangiocarcinoma” carcinogenesis pathways consist of mechanical damage to the bile duct epithelium, immunopathologic and cellular reactions to the liver fluke’s antigens and excretory/secretory products, liver fluke-induced changes in the biliary tract microbiome and the effects of repeated treatment for liver fluke. A vaccine and novel biomarkers are needed for the primary and secondary prevention of CCA in endemic areas. Importantly, climate change exerts an effect on vector-borne parasitic diseases, and awareness of liver fluke should be enhanced in potentially migrated habitat areas.

Concepts: Immune system, Digestive system, Liver, Hepatology, Bile duct, Gallbladder, Cholangiocarcinoma, Primary sclerosing cholangitis

32

A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.

Concepts: Cell, Developmental biology, Stem cell, Liver, Organ, Organ transplant, Induced pluripotent stem cell, Gallbladder

31

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

Concepts: Liver, Regeneration, Organ, Glycogen, Bile, Peritoneum, Gallbladder, Hepatocyte

28

This review summarizes recent innovations in the approaches to gallbladder disease, including laparoscopic cholecystectomy, cholecystectomy with natural orifice transluminal endoscopic surgery, percutaneous cholecystostomy, and peroral endoscopic gallbladder drainage.

Concepts: Surgery, Laparoscopic surgery, Gallbladder, Cholecystectomy, Endoscopic retrograde cholangiopancreatography, Endoscopy, Common hepatic duct, Cystic duct

28

Cholangiocytes, the cells lining bile ducts, are a heterogenous, highly dynamic population of epithelial cells. While these cells comprise a small fraction of the total cellular component of the liver, they perform the essential role of bile modification and transport of biliary and blood constituents. From a pathophysiological standpoint, cholangiocytes are the target of a diverse group of biliary disorders, collectively referred to as the cholangiopathies. To date, the cause of most cholangiopathies remains obscure. It is known, however, that cholangiocytes exist in an environment rich in potential mediators of cellular injury, express receptors that recognize potential injurious insults, and participate in portal tract repair processes following hepatic injury. As such, cholangiocytes may not be only a passive target, but are likely directly and actively involved in the pathogenesis of cholangiopathies. Here, we briefly summarize the characteristics of the reactive cholangiocyte and cholangiocyte responses to potentially injurious endogenous and exogenous molecules, and in addition, present emerging concepts in our understanding of the etiopathogenesis of several cholangiopathies.

Concepts: Digestive system, Epithelium, Liver, Tissues, Bile, Connective tissue, Bile duct, Gallbladder

28

Phosphorylation of the RelA subunit at serine 536 (RelA-P-Ser536) is important for hepatic myofibroblast survival and is mechanistically implicated in liver fibrosis. Here, we show that a cell-permeable competing peptide (P6) functions as a specific targeted inhibitor of RelA-P-Ser536 in vivo and exerts an antifibrogenic effect in two progressive liver disease models, but does not impair hepatic inflammation or innate immune responses after lipopolysaccharide challenge. Using kinase assays and western blotting, we confirm that P6 is a substrate for the inhibitory kappa B kinases (IKKs), IKKα and IKKβ, and, in human hepatic myofibroblasts, P6 prevents RelA-P-Ser536, but does not affect IKK activation of IκBα. We demonstrate that RelA-P-Ser536 is a feature of human lung and skin fibroblasts, but not lung epithelial cells, in vitro and is present in sclerotic skin and diseased lungs of patients suffering from idiopathic pulmonary fibrosis. Conclusion: RelA-P-Ser536 may be a core fibrogenic regulator of fibroblast phenotype. (HEPATOLOGY 2013).

Concepts: Immune system, Cancer, Signal transduction, Lung, Innate immune system, Epithelium, Cirrhosis, Gallbladder

28

We aimed to analyze the image quality, CT number, artifacts, radiation dose reduction, and coverage in abdominal virtual unenhanced (VU) and conventional unenhanced (CU) data sets obtained with a second-generation dual-energy computed tomography and to compare the sensitivity of VU and CU data sets for liver lesion detection.

Concepts: Gallbladder

28

: To investigate the risk of intestinal cancer in a cohort of people who had undergone cholecystectomy for gallstones, and in a cohort of people who had been hospitalized for gallbladder disease but had not undergone cholecystectomy.

Concepts: Epidemiology, Cancer, Actuarial science, Liver, Hepatology, Gallbladder, Common hepatic duct, Cystic duct