scholarly journals If It Looks Like a Duct and Acts Like a Duct: On the Role of Reprogrammed Hepatocytes in Cholangiopathies

2020 ◽  
Vol 20 (1) ◽  
pp. 19-23 ◽  
Author(s):  
Kari Nejak-Bowen
Keyword(s):  
Bile Flow ◽  
Therapeutic Strategy ◽  
De Novo ◽  
Biliary Tree ◽  
Cellular Reprogramming ◽  
Cholestatic Liver Disease ◽  
Cell Type ◽  
Biliary Epithelium ◽  
End Stage

Cholangiopathies are chronic, progressive diseases of the biliary tree, and can be either acquired or genetic. The primary target is the cholangiocyte (CC), the cell type lining the bile duct that is responsible for bile modification and transport. Despite advances in our understanding and diagnosis of these diseases in recent years, there are no proven therapeutic treatments for the majority of the cholangiopathies, and liver transplantation is the only life-extending treatment option for patients with end-stage cholestatic liver disease. One potential therapeutic strategy is to facilitate endogenous repair of the biliary system, which may alleviate intrahepatic cholestasis caused by these diseases. During biliary injury, hepatocytes (HC) are known to alter their phenotype and acquire CC-like features, a process known as cellular reprogramming. This brief review discusses the potential ways in which reprogrammed HC may contribute to biliary repair, thereby restoring bile flow and reducing the severity of cholangiopathies. Some of these include modifying bile to reduce toxicity, serving as a source of de novo CC to repair the biliary epithelium, or creating new channels to facilitate bile flow.

scholarly journals Large-duct cholangiopathies: aetiology, diagnosis and treatment

2019 ◽  
Vol 10 (3) ◽  
pp. 284-291 ◽  
Author(s):  
Shyam Menon ◽  
Andrew Holt
Keyword(s):  
Bile Flow ◽  
Biliary Tree ◽  
Biliary Cirrhosis ◽  
Caroli Disease ◽  
End Stage Liver Disease ◽  
Recurrent Pyogenic Cholangitis ◽  
Chronic Cholestasis ◽  
End Stage ◽  
Extrahepatic Biliary Tree ◽  
Portal Biliopathy

Cholangiopathies describe a group of conditions affecting the intrahepatic and extrahepatic biliary tree. Impairment to bile flow and chronic cholestasis cause biliary inflammation, which leads to more permanent damage such as destruction of the small bile ducts (ductopaenia) and biliary cirrhosis. Most cholangiopathies are progressive and cause end-stage liver disease unless the physical obstruction to biliary flow can be reversed. This review considers large-duct cholangiopathies, such as primary sclerosing cholangitis, ischaemic cholangiopathy, portal biliopathy, recurrent pyogenic cholangitis and Caroli disease.

scholarly journals Ectopic trkA expression mediates a NGF survival response in NGF-independent sensory neurons but not in parasympathetic neurons.

1993 ◽  
Vol 123 (6) ◽  
pp. 1555-1566 ◽  
Author(s):  
T E Allsopp ◽  
M Robinson ◽  
S Wyatt ◽  
A M Davies
Keyword(s):  
Neurotrophic Factor ◽  
De Novo ◽  
Experimental Demonstration ◽  
Cell Type ◽  
Rt Pcr ◽  
Ngf Receptor ◽  
Parasympathetic Neurons ◽  
Signal Transduction Event ◽  
Embryonic Neurons

We have investigated the role of trkA, the tyrosine kinase NGF receptor, in mediating the survival response of embryonic neurons to NGF. Embryonic trigeminal mesencephalic (TMN) neurons, which normally survive in the presence of brain-derived neurotrophic factor (BDNF) but not NGF, become NGF-responsive when microinjected with an expression vector containing trkA cDNA. In contrast, microinjection of ciliary neurotrophic factor (CNTF)-dependent embryonic ciliary neurons with the same construct does not result in the acquisition of NGF responsiveness by these neurons despite de novo expression of trkA mRNA and protein. The failure of trkA to result in an NGF-promoted survival response in ciliary neurons is not due to absence of the low-affinity NGF receptor, p75, in these neurons. Quantitative RT/PCR and immunocytochemistry showed that TMN and ciliary neurons both express p75 mRNA and protein. These findings not only provide the first direct experimental demonstration of trkA mediating a physiological response in an appropriate cell type, namely NGF-promoted survival of embryonic neurons, but indicate that not all neurons are able to respond to a trkA-mediated signal transduction event.

A Potential Profibrogenic Role of Biliary Epithelium-Derived Cardiotrophin-1 in Pediatric Cholestatic Liver Disease

2015 ◽  
Vol 35 (8) ◽  
pp. 606-612 ◽  
Author(s):  
Xiangwei Hua ◽  
Yuhua Shan ◽  
Dawei Li ◽  
Dongwei Xu ◽  
Jiang Zhang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Cholestatic Liver Disease ◽  
Biliary Epithelium

scholarly journals Dual Role of Bile Acids on the Biliary Epithelium: Friend or Foe?

2019 ◽  
Vol 20 (8) ◽  
pp. 1869 ◽  
Author(s):  
Leonardo Baiocchi ◽  
Tianhao Zhou ◽  
Suthat Liangpunsakul ◽  
Ilaria Lenci ◽  
Francesco Santopaolo ◽  
...  
Keyword(s):  
Bile Acids ◽  
Liver Diseases ◽  
Biliary Tree ◽  
Chronic Liver Diseases ◽  
Biliary Epithelium ◽  
Hydrophobic Compounds ◽  
Human Disorders ◽  
Molecular Aspects ◽  
Cell Signaling Pathways

Bile acids are a family of amphipathic compounds predominantly known for their role in solubilizing and absorbing hydrophobic compounds (including liposoluble vitamins) in the intestine. Bile acids also are key signaling molecules and inflammatory agents that activate transcriptional factors and cell signaling pathways that regulate lipid, glucose, and energy metabolism in various human disorders, including chronic liver diseases. However, in the last decade increased awareness has been founded on the physiological and chemical heterogeneity of this category of compounds and their possible beneficial or injurious effects on the biliary tree. In this review, we provide an update on the current understanding of the molecular mechanism involving bile acid and biliary epithelium. The last achievements of the research in this field are summarized, focusing on the molecular aspects and the elements with relevance regarding human liver diseases.

Bile secretory function of intrahepatic biliary epithelium in the rat

1989 ◽  
Vol 257 (1) ◽  
pp. G124-G133 ◽  
Author(s):  
G. Alpini ◽  
R. Lenzi ◽  
W. R. Zhai ◽  
P. A. Slott ◽  
M. H. Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Biliary Obstruction ◽  
Bile Flow ◽  
Secretory Activity ◽  
Biliary Tree ◽  
Cell Hyperplasia ◽  
Bile Formation ◽  
Biliary Epithelium ◽  
Biliary Epithelial Cells ◽  
Ductular Cell

To shed light on ductular fluid secretion, hepatic histology and ultrastructure, cell proliferation and phenotypes, and several aspects of biliary physiology were studied in rats with ductular cell hyperplasia induced by either biliary obstruction (0-14 days) or 1-naphthylisothiocyanate (ANIT) feeding (0-28 days). In both groups of experimental animals, bile duct hyperplasia and spontaneous bile flow and secretin-induced choleresis increased with time of treatment in a linear fashion. Measurements of [14C]mannitol biliary entry and of biliary tree volume showed that the increase in both spontaneous and secretin-stimulated bile flow originated at the proliferated biliary structures. Ultrastructural examination, [3H]thymidine incorporation, and histochemical and immunohistochemical staining for various markers demonstrated that in both hyperplastic reactions the proliferated cells were the progeny of preexisting biliary epithelial cells and retained their characteristics. These results indicate that the increased bile secretory activity associated with either biliary obstruction or ANIT intoxication reflects a quantitative change due to the proliferation of biliary epithelial cells. Thus both models of bile ductular cell hyperplasia lend themselves to assessment of the transport function of intrahepatic biliary epithelium and its contribution to normal bile formation. In the present studies, we have estimated that net ductular secretion in the normal rat accounts for 10-13% of spontaneously secreted hepatic bile.

scholarly journals Novel findings from family-based exome sequencing for children with biliary atresia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kien Trung Tran ◽  
Vinh Sy Le ◽  
Lan Thi Mai Dao ◽  
Huyen Khanh Nguyen ◽  
Anh Kieu Mai ◽  
...  
Keyword(s):  
Biliary Atresia ◽  
Exome Sequencing ◽  
Bile Flow ◽  
De Novo ◽  
Biliary Tree ◽  
Mendelian Inheritance ◽  
Genome Project ◽  
Blood Samples ◽  
Whole Exome ◽  
Family Based

AbstractBiliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.

scholarly journals Novel Findings From Family-based Exome Sequencing for Children With Biliary Atresia

2021 ◽  
Author(s):  
Kien Tran ◽  
Vinh Le ◽  
Lan Dao ◽  
Huyen Nguyen ◽  
Anh Mai ◽  
...  
Keyword(s):  
Biliary Atresia ◽  
Exome Sequencing ◽  
Bile Flow ◽  
Somatic Mutations ◽  
De Novo ◽  
Biliary Tree ◽  
Mendelian Inheritance ◽  
Genome Project ◽  
Whole Exome ◽  
Family Based

Abstract Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree, characterized by the obstruction of bile flow led to liver failure, scarring and cirrhosis. This study aimed to explore the elusive etiology of BA by conducting whole exome sequencing (WES) for 41 children with BA and their parents (35 trios, including one family with two BA diagnosed children and five child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, six de novo and five homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and having a low minor allele frequency against three employed databases: Kinh Vietnamese (KHV), gnomad and 1000 Genome project. Interestingly, AMER1, INVS and OCRL variants were repeatedly found in unrelated probands, and were firstly reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic mutations were unlikely to occur during the morphogenesis. In agreement with earlier attempts, this study implicated a genetical heterogeneity and non-Mendelian inheritance of BA.

scholarly journals The First Report of Multicentric Carpotarsal Osteolysis Syndrome Caused by MAFB Mutation in Asian

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Pongsakorn Choochuen ◽  
Kitiwan Rojneuangnit ◽  
Thanitchet Khetkham ◽  
Sookkasem Khositseth
Keyword(s):  
Genetic Study ◽  
De Novo ◽  
Molecular Genetic ◽  
Osteoclast Differentiation ◽  
Female Adolescent ◽  
De Novo Mutation ◽  
Molecular Genetic Study ◽  
Stage Renal Disease ◽  
End Stage

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by aggressive osteolysis associated with progressive nephropathy. The early clinical presentation can mimic polyarticular juvenile idiopathic arthritis. Since 2012, MAFB mutations have been discovered in all MCTO patients. Therefore, the early diagnosis can be made based on genetic confirmation. We report the clinical manifestation of mineral bone disease and the molecular genetic study of a Thai female adolescent with MCTO. She presented with end-stage renal disease, bilateral wrist and ankle joint deformities, and subtle facial dysmorphic features. We identified a heterozygous missense MAFB mutation at nucleotide 197 from C to G (NM_005461.4; c.197C>G), predicting the change of amino acid at codon 66 from serine to cysteine (p.Ser66Cys), and the mutation was absent in the parents, indicating a de novo mutation. This report confirms the previous link between MAFB mutation and MCTO. Her unexplained hypercalcemia after a regular dose of calcium and active vitamin D supported an important role of MafB in the negative regulation of RANKL-mediated osteoclast differentiation. Therefore, we would encourage the physicians who take care of MCTO patients to closely monitor serum calcium level and perform a genetic study as a part of the management and investigation.

scholarly journals Biliary atresia: pathology, etiology and pathogenesis

2020 ◽  
Vol 6 (5) ◽  
pp. FSO466
Author(s):  
Mukul Vij ◽  
Mohamed Rela
Keyword(s):  
Biliary Atresia ◽  
Bile Flow ◽  
Biliary Tree ◽  
Giant Cells ◽  
Biliary Epithelium ◽  
Liver Biopsies ◽  
Portal Tracts ◽  
Ductular Proliferation ◽  
Th1 Immune Response ◽  
Multinucleate Giant Cells

Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice. Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen. Lobular morphological features may include variable multinucleate giant cells, bilirubinostasis and hemopoiesis. The etiopathogenesis of biliary atresia is multifactorial and multiple pathomechanisms have been proposed. Experimental and clinical studies have suggested that viral infection initiates biliary epithelium destruction and release of antigens that trigger a Th1 immune response, which leads to further injury of the bile duct, resulting in inflammation and obstructive scarring of the biliary tree. It has also been postulated that biliary atresia is caused by a defect in the normal remodelling process. Genetic predisposition has also been proposed as a factor for the development of biliary atresia.

Posttransplant CMV infection and the role of immunosuppression (Sponsor: Novartis Pharma GmbH, Nürnberg)

2016 ◽  
Vol 04 (01) ◽  
pp. 4-10
Keyword(s):  
Lower Incidence ◽  
Paradigm Shift ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Expert Panel ◽  
Risk Of Infection ◽  
Cmv Infection ◽  
Expert Meeting ◽  
Selection Of

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.

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