Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

Hargrove, Laura; Kennedy, Lindsey; Demieville, Jennifer; Jones, Hannah; Meng, Fanyin; DeMorrow, Sharon; Karstens, Walker; Madeka, Taronish; Greene, John F.; Francis, Heather

doi:10.1002/hep.29079

Cited by 60 publications

(126 citation statements)

References 48 publications

(160 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…Instead, the collagen content (as marked by hydroxyproline content) was somewhat higher in the MC‐deficient as compared with the MC‐competent rats, indicating a protective role of MCs . In contrast to these studies, the extent of liver fibrosis developing after bile duct ligation was reduced in MC‐deficient W sh /W sh mice in comparison with MC‐sufficient controls …”

Section: Mast Cells In Models Of Liver Fibrosiscontrasting

confidence: 63%

See 1 more Smart Citation

The controversial role of mast cells in fibrosis

Bradding

Pejler

2018

Immunological Reviews

113

View full text Add to dashboard Cite

Fibrosis is a medical condition characterized by an excessive deposition of extracellular matrix compounds such as collagen in tissues. Fibrotic lesions are present in many diseases and can affect all organs. The excessive extracellular matrix accumulation in these conditions can often have serious consequences and in many cases be life-threatening. A typical event seen in many fibrotic conditions is a profound accumulation of mast cells (MCs), suggesting that these cells can contribute to the pathology. Indeed, there is now substantialv evidence pointing to an important role of MCs in fibrotic disease. However, investigations from various clinical settings and different animal models have arrived at partly contradictory conclusions as to how MCs affect fibrosis, with many studies suggesting a detrimental role of MCs whereas others suggest that MCs can be protective. Here, we review the current knowledge of how MCs can affect fibrosis.

show abstract

Section: Mast Cells In Models Of Liver Fibrosiscontrasting

confidence: 63%

“…202 In contrast to these studies, the extent of liver fibrosis developing after bile duct ligation was reduced in MC-deficient W sh /W sh mice in comparison with MC-sufficient controls. 206…”

Section: Mast Cells In Models Of Liver Fibrosismentioning

confidence: 99%

The controversial role of mast cells in fibrosis

Bradding

Pejler

2018

Immunological Reviews

113

View full text Add to dashboard Cite

show abstract

“…Another study has shown that serum levels of histamine are increased in Mdr2 −/− mice, and inhibition of mast cell-derived histamine secretion decreases serum histamine levels as well as bile duct hyperplasia and fibrosis in these mice [70]. Mast cell-deficient mice show less liver damage, bile duct mass, and fibrosis during BDL compared to wild-type [71]. These studies suggest that histamine secreted from mast cells infiltrated during cholestatic liver injury interacts with histamine receptors and regulates cholangiocyte responses leading to bile duct hyperplasia and fibrosis.…”

Section: Pathways Associated With Cholangiocyte Responses and Theimentioning

confidence: 99%

Mechanisms of cholangiocyte responses to injury

Sato

Meng²,

Giang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

show abstract

“…SCF receptor) on their surface [12,13]. We have demonstrated that, during PSC (both in rodent models and human liver tissues), MC infiltration increases and MCs reside close by bile ducts, allowing for an interaction with cholangiocytes [11,14]. Additionally, it has been shown that cholangiocytes secrete increased amounts of SCF during damage such as cholangiocarcinoma (CCA) and during liver regeneration [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…After migration to the liver, MCs contribute to hepatic fibrosis by promoting HSC activation and also play a role in enhancing inflammation [11,14,17]. Multiple studies from our group have demonstrated how inhibition of MC mediators (i.e.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2−/− mice

Meadows

Kennedy

Hargrove

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

A B S T R A C TPrimary sclerosing cholangitis (PSC) is characterized by increased mast cell (MC) infiltration, biliary damage and hepatic fibrosis. Cholangiocytes secrete stem cell factor (SCF), which is a chemoattractant for c-kit expressed on MCs. We aimed to determine if blocking SCF inhibits MC migration, biliary damage and hepatic fibrosis. Methods: FVB/NJ and Mdr2 −/− mice were treated with Mismatch or SCF Vivo-Morpholinos. We measured (i) SCF expression and secretion; (ii) hepatic damage; (iii) MC migration/activation and histamine signaling; (iv) ductular reaction and biliary senescence; and (v) hepatic fibrosis. In human PSC patients, SCF expression and secretion were measured. In vitro, cholangiocytes were evaluated for SCF expression and secretion. Biliary proliferation/senescence was measured in cholangiocytes pretreated with 0.1% BSA or the SCF inhibitor, ISK03. Cultured HSCs were stimulated with cholangiocyte supernatant and activation measured. MC migration was determined with cholangiocytes pretreated with BSA or ISK03 loaded into the bottom of Boyden chambers and MCs into top chamber. Results: Biliary SCF expression and SCF serum levels increase in human PSC. Cholangiocytes, but not hepatocytes, from SCF Mismatch Mdr2 −/− mice have increased SCF expression and secretion. Inhibition of SCF in Mdr2 −/− mice reduced (i) hepatic damage; (ii) MC migration; (iii) histamine and SCF serum levels; and (iv) ductular reaction/biliary senescence/hepatic fibrosis. In vitro, cholangiocytes express and secrete SCF. Blocking stellate cell; hHSC, human hepatic stellate cell; IBDM, intrahepatic bile duct mass; Ki-67, marker of proliferation; MC, mast cell; Mdr2 −/− , multidrug resistance transporter 2/ABC transporter B family member 2 knock out; mMCP-1, mouse mast cell protease 1; p16, cyclin-dependent kinase inhibitor 2A; p18, Cyclin-dependent kinase 4 inhibitor C; PCNA, proliferating cell nuclear antigen; PSC, primary sclerosing cholangitis; qPCR, quantitative PCR; SASP, senescence-associate secretory phenotype; SCF, stem cell factor; SYP-9, synaptophysin 9; WT, wild type ☆ 0925-4439/ Published by Elsevier B.V.T biliary SCF decreased MC migration, biliary proliferation/senescence, and HSC activation. Conclusion: Cholangiocytes secrete increased levels of SCF inducing MC migration, contributing to biliary damage/hepatic fibrosis. Targeting MC infiltration may be an option to ameliorate PSC progression.

show abstract

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

Cited by 60 publications

References 48 publications

The controversial role of mast cells in fibrosis

The controversial role of mast cells in fibrosis

Mechanisms of cholangiocyte responses to injury

Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2−/− mice

Contact Info

Product

Resources

About