Functional and Structural Features of Cholangiocytes in Health and Disease

Maroni, Luca; Bai, Haibo; Ray, Debolina; Zhou, Tianhao; Wan, Ying; Meng, Fanyin; Marzioni, Marco; Alpini, Gianfranco

doi:10.1016/j.jcmgh.2015.05.005

Cited by 95 publications

(119 citation statements)

References 138 publications

(179 reference statements)

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“…The results suggest a decrease in cholangiocyte proliferation and bile acid reuptake (Lazaridis et al, 1997). The expected consequence of downregulated Tgr5 in hFRGN livers is a reduction of the cholehepatic shunt, leading to higher bile acid concentration in bile and the possibility of generating cystic fibrosis or primary sclerosing cholangitis characteristics (Glaser and Alpini, 2009;Maroni et al, 2015).…”

Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 93%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah2/2), recombination activating gene 2 (Rag22/2), and interleukin 2 receptor subunit gamma (IL-2rg 2/2) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids) but lower transforming growth factor beta receptor 2 (TGFBR2) mRNA expression levels (10%) in human hepatocytes and other proliferative markers in mouse nonparenchymal cells (Tgf-b1) and cholangiocytes [plasma membrane-bound, G protein-coupled receptor for bile acids (Tgr5)], suggestive of irregular regeneration processes in hFRGN livers. Changes in gene expression in murine intestine, kidney, and brain of hFRGN mice, in particular, induction of intestinal farnesoid X receptor (Fxr) genes: fibroblast growth factor 15 (Fgf15), mouse ileal bile acid binding protein (Ibabp), small heterodimer partner (Shp), and the organic solute transporter alpha (Osta), were observed. Proteomics revealed persistence of remnant murine proteins (cyotchrome P450 7a-hydroxylase (Cyp7a1) and other enzymes and transporters) in hFRGN livers and suggest the likelihood of mouse activity. When compared with normal human liver tissue, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tb-and ta-muricholic acid-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver fibroblast growth factor receptor 4 (FGFR4), as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, making questionable the use of the preparation for drug metabolism studies.

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Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 93%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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“…The autonomic innervation: (1) sustains cholangiocyte proliferation and prevent apoptosis in response to injury; (2) maintain an adequate bile acids transporter (ASBT) in cholangiocytes. Development of non-anastomotic biliary strictures in the transplanted liver occurs as a consequence of impaired hepatocellular transporters 74,75…”

Section: Discussionmentioning

confidence: 99%

Biology of Cholangiocytes: From Bench to Bedside

2016

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Cholangiocytes, the lining epithelial cells in bile ducts, are an important subset of liver cells. They are activated by endogenous and exogenous stimuli and are involved in the modification of bile volume and composition. They are also involved in damaging and repairing the liver. Cholangiocytes have many functions including bile production. They are also involved in transport processes that regulate the volume and composition of bile. Cholangiocytes undergo proliferation and cell death under a variety of conditions. Cholangiocytes have functional and morphological heterogenecity. The immunobiology of cholangiocytes is important, particularly for understanding biliary disease. Secretion of different proinflammatory mediators, cytokines, and chemokines suggests the major role that cholangiocytes play in inflammatory reactions. Furthermore, paracrine secretion of growth factors and peptides mediates extensive cross-talk with other liver cells, including hepatocytes, stellate cells, stem cells, subepithelial myofibroblasts, endothelial cells, and inflammatory cells. Cholangiopathy refers to a category of chronic liver diseases whose primary disease target is the cholangiocyte. Cholangiopathy usually results in end-stage liver disease requiring liver transplant. We summarize the biology of cholangiocytes and redefine the concept of cholangiopathy. We also discuss the recent progress that has been made in understanding the pathogenesis of cholangiopathy and how such progress has influenced therapy.

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“…During development these two cell types are derived from the hepatoblast, a bipotential progenitor (1)(Figure 1A). Hepatocytes perform liver metabolic functions, including secretion of bile, and bile duct epithelial cells serve as a conduit for bile to drain from the liver as well as playing an active role in modifying bile composition (2, 3). Mouse studies using genetic reporters to trace hepatocyte lineage demonstrate that adult hepatic cell turnover is slow.…”

Section: Regenerative Capacity Of the Hepatocytementioning

confidence: 99%

Emerging advancements in liver regeneration and organogenesis as tools for liver replacement

Huppert

Campbell²

2016

Current Opinion in Organ Transplantation

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Purpose of review Although the liver possesses a unique, innate ability to regenerate through mass compensation, transplantation remains the only therapy when damage outpaces regeneration, or liver metabolic capacity is irreversibly impacted. Recent insight from developmental biology has greatly influenced the advancement of alternative options to transplantation in these settings. Recent findings Factors known to direct liver cell specification, expansion, and differentiation have been used to generate hepatocyte-like cells from stem and somatic cells for cell therapies. Additionally, interactions between hepatic epithelial and non-epithelial cells key to establishing hepatic architecture have been used in tissue engineering approaches to develop self-organizing hepatic organoids and bio-artificial liver devices. Simultaneously, recent clinically applicable advances in human hepatocyte transplantation and promotion of innate hepatic regeneration have been limited. Summary Although mature hepatocytes have the potential to bridge or replace whole organ transplantation, limits in the ability to obtain healthy cells, stabilize in vitro expansion, cryopreservation, and alleviate rejection, still exist. Alternative sources for generating hepatocytes hold promise for cell therapy and tissue engineering. These may allow generation of autologous or universal donor cells that eliminate the need for immunosuppression; however, limits exist regarding hepatocyte maturity and efficacy at liver repopulation, as well as applicability to human chronic liver disease.

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Functional and Structural Features of Cholangiocytes in Health and Disease

Cited by 95 publications

References 138 publications

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Biology of Cholangiocytes: From Bench to Bedside

Emerging advancements in liver regeneration and organogenesis as tools for liver replacement

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