CCN1 induces hepatic ductular reaction through integrin αvβ5–mediated activation of NF-κB

Kim, Ki‐Hyun; Chen, Chih Chiun; Alpini, Gianfranco; Lau, Lester F.

doi:10.1172/jci79327

Cited by 91 publications

(120 citation statements)

References 74 publications

(100 reference statements)

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“…Another diet model that is commonly used in mice is the modified cholinedeficient ethionine diet devel oped by the Yeoh Group 39 , which induces hepato cellular injury with a degree of steatosis and a secondary ductular response in which ductular cells (broadly com parable to oval cells in the rat) spread from the portal tract 37,40,41 . These ductular reactions are important for biliary regener ation after injury and, if their prolifer ative response is impaired following biliary injury, then there is an increase in hepatic necrosis 42 . Whether the ductular reactions contain bipotential HPCs capable of regener ating hepatocytes as well as biliary cells is a controver sial area.…”

Section: Key Pointsmentioning

confidence: 99%

Liver regeneration — mechanisms and models to clinical application

Forbes

Newsome

2016

Nat Rev Gastroenterol Hepatol

322

296

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Although the normal liver has a fantastic regenerative capacity, following acute injury or resection this regener ative ability becomes overwhelmed in two important scenarios: in the setting of severe acute liver injury or when there is severe chronic liver injury with aberrant liver architecture and marked liver fibrosis 1,2 . These scenarios are clinically relevant and often result in serious morbidity and mortality 3 . While there have been decades of excellent and clinically informative research into understanding the signals that control regener ation of the normal liver 4 , the mechanisms at play when the abnor mal liver attempts regeneration are less well described 5 . Understanding how regeneration fails or is impaired in the severely damaged liver is an important goal. Lessons learned from relevant animal models might have impor tance in the clinical setting and aid the develop ment of new therapies to either promote regener ation or prevent complications that arise during the period of liver regeneration.A clinical scenario in which an improved understand ing of regeneration of the compromised liver would be of benefit includes liver transplantation, here the increas ingly common use of partial liver grafts such as split livers and living donor transplants relies upon regener ation of the donor graft to reach the correct liver mass 6 .Failure of regeneration in these settings results in poor or delayed graft function, prolonged intensive care stays, occasionally a requirement for retransplantation or, ulti mately, even death of the recipient 7,8 . By understanding the pathological mechanisms driving these adverse con ditions it is hoped that the period of regeneration can be more predictable and the associated clinical complications ultimately preventable. The ability to predict or improve liver regeneration when the liver is compromised -for example, in the setting of cirrhosis when surgical resection of hepatocellular cancer (HCC) is commonly performed, or following the resection of colorectal hepatic metastasis, when the liver has received prior chemotherapy -would enable clinicians to optimize cancer resection approaches. Furthermore, by understanding the mechanisms under lying normal liver regeneration and aberrant liver regener ation in chronic liver injury it is hoped that we will be able to promote 'healthy regeneration' or remodel ling in chronic liver disease. Such a scenario in which this approach could be applied includes liver cirrhosis. Here, the initial insult (such as viral hepatitis or autoimmune hepatitis) can sometimes be directly treated, but the liver tissue is left severely damaged and still susceptible to the clinical consequences of liver failure, portal hypertension and an increased risk of HCC 9 .Abstract | Liver regeneration has been studied for many decades and the mechanisms underlying regeneration of the normal liver following resection or moderate damage are well described. A large number of factors extrinsic (such as bile acids and circulating growth factors) and intrinsi...

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Section: Key Pointsmentioning

confidence: 99%

Liver regeneration — mechanisms and models to clinical application

Forbes

Newsome

2016

Nat Rev Gastroenterol Hepatol

322

296

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“…The initial reactions of cholangiocytes in the cholestatic injuries are called as “ductular reactions”. “Ductular reactions” are characterized by cholangiocyte proliferation, expansion of transit-amplifying cells or hepatic progenitor cells (HPCs), and differentiation of the biopotential HPCs into cholangiocytes (Kim et al, 2015). These reactions are also observed in human liver diseases (Gouw et al, 2011).…”

Section: New Insights Into Apf Biologymentioning

confidence: 99%

“…Kim et al reported that hepatic myofibroblasts’ Jag1 expression causes cholangiocyte differentiation and proliferation and that the signal contributes to cholangiocyte injury through JAG/NOTCH signaling pathways (Kim et al, 2015). Ongoing experiments to look at growth hormones and chemokines expressed by cholangiocytes and aPFs/myofibroblasts will shed new light on the complex command and control system by which these communicate within the normal and after biliary injury.…”

Section: New Insights Into Apf Biologymentioning

confidence: 99%

The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis

et al. 2016

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Liver fibrosis results from chronic injury of hepatocytes and activation of Collagen Type I producing myofibroblasts that produce fibrous scar in liver fibrosis. Myofibroblasts are not present in the normal liver but rapidly appear early in experimental and clinical liver injury. The origin of the myofibroblast in liver fibrosis is still unresolved. The possibilities include activation of liver resident cells including portal fibroblasts, hepatic stellate cells, mesenchymal progenitor cells, and fibrocytes recruited from the bone marrow. It is considered that hepatic stellate cells and portal fibroblasts are the major source of hepatic myofibroblasts. In fact, the origin of myofibroblasts differs significantly for chronic liver diseases of different etiologies, such as cholestatic liver disease or hepatotoxic liver disease. Depending on etiology of hepatic injury, the fibrogenic foci might initiate within the hepatic lobule as seen in chronic hepatitis, or primarily affect the portal areas as in most biliary diseases. It has been suggested that activated portal fibroblasts/myofibroblasts work as “myofibroblasts for cholangiocytes” while hepatic stellate cells work as “myofibroblast for hepatocytes”. This review will focus on our current understanding of the activated portal fibroblasts/myofibroblasts in cholestatic liver fibrosis.

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“…Given the fact that liver fibrosis occurs as a final outcome of an abnormal wound healing response and is closely associated with HPC activation and ductular reactions during chronic liver disease, we speculate that the CCN proteins also regulate HPC activation. In supporting this notion, a recent report identifies CCN1/CYR61 as a critical regulator in biliary injury repair through the integrin α v β 5/NF- κ B/JAG1 signaling axis [41]. CCN1/CYR61 stimulates Jag1 expression in hepatic stellate cells and promotes HPC differentiation, cholangiocyte proliferation, and ductular reactions [41].…”

Section: Discussionmentioning

confidence: 99%

“…In supporting this notion, a recent report identifies CCN1/CYR61 as a critical regulator in biliary injury repair through the integrin α v β 5/NF- κ B/JAG1 signaling axis [41]. CCN1/CYR61 stimulates Jag1 expression in hepatic stellate cells and promotes HPC differentiation, cholangiocyte proliferation, and ductular reactions [41]. CCN2/CTGF is another member involved in HPC activation and ductular reactions.…”

Section: Discussionmentioning

confidence: 99%

Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma

Jorgensen

Song

et al. 2016

Gastroenterology Research and Practice

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Hepatic stem/progenitor cells (HPC) reside quiescently in normal biliary trees and are activated in the form of ductular reactions during severe liver damage when the replicative ability of hepatocytes is inhibited. HPC niches are full of profibrotic stimuli favoring scarring and hepatocarcinogenesis. The Cyr61/CTGF/NOV (CCN) protein family consists of six members, CCN1/CYR61, CCN2/CTGF, CCN3/NOV, CCN4/WISP1, CCN5/WISP2, and CCN6/WISP3, which function as extracellular signaling modulators to mediate cell-matrix interaction during angiogenesis, wound healing, fibrosis, and tumorigenesis. This study investigated expression patterns of CCN proteins in HPC and cholangiocarcinoma (CCA). Mouse HPC were induced by the biliary toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Differential expression patterns of CCN proteins were found in HPC from DDC damaged mice and in human CCA tumors. In addition, we utilized reporter mice that carried Ccn2/Ctgf promoter driven GFP and detected strong Ccn2/Ctgf expression in epithelial cell adhesion molecule (EpCAM)+ HPC under normal conditions and in DDC-induced liver damage. Abundant CCN2/CTGF protein was also found in cytokeratin 19 (CK19)+ human HPC that were surrounded by α-smooth muscle actin (α-SMA)+ myofibroblast cells in intrahepatic CCA tumors. These results suggest that CCN proteins, particularly CCN2/CTGF, function in HPC activation and CCA development.

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CCN1 induces hepatic ductular reaction through integrin αvβ5–mediated activation of NF-κB

Cited by 91 publications

References 74 publications

Liver regeneration — mechanisms and models to clinical application

Liver regeneration — mechanisms and models to clinical application

The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis

Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma

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