Stellate Cells, Portal Myofibroblasts, and Epithelial-to-Mesenchymal Transition

Koyama, Yukinori; Wang, Ping; Brenner, David A.; Kisseleva, Tatiana

doi:10.1016/b978-0-12-800134-9.00006-3

Cited by 8 publications

(16 citation statements)

References 146 publications

(209 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While activation of portal fibroblasts to fibrogenic myofibroblasts is an important component of biliary fibrosis [ 22 ], overwhelming evidence indicates that the perisinusoidal hepatic stellate cells (HSCs) are the major source of liver fibrosis of any etiology [ 22 , 23 ]. During liver injury, HSCs transdifferentiate from their quiescent physiologic to the fibrogenic phenotype.…”

Section: Resultsmentioning

confidence: 99%

Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice

et al. 2016

View full text Add to dashboard Cite

Why only a subpopulation (about 15%) of humans develops liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR) protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8–10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and fibrosis were quantified. The mRNA expression of alcohol dehydrogenase-1, acetaldehyde dehydrogenase-1 and cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and inflammation, prominent ductular proliferation, and robust fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic iron accumulation, robust lipid peroxidation and mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human alcoholic liver cirrhosis were associated with increased iron content, reduced expression of alcohol dehydrogenase and acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic fibrosis/cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and iron homeostasis, mitochondrial damage and oxidative injury.

show abstract

Section: Resultsmentioning

confidence: 99%

Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Pfb are important in the early stages of the disease, but HSCs are predominantly responsible for the progression of the disease, even for biliary fibrosis. 1,2 …”

mentioning

confidence: 99%

Hepatic stellate cell activation and pro-fibrogenic signals

Gandhi

2017

Journal of Hepatology

120

122

View full text Add to dashboard Cite

“…Elimination of the injury stimulus causes aHSCs to undergo apoptosis (72), senescence (73), or reversal to quiescent or the so-called "inhibited phenotype" (iHSC) leading to regression of fibrosis (8,13,(74)(75)(76). IL10 and IL22 can be critically involved in the fibrosis reversal process as evidenced by IL10-induced inhibition of the expression of the activation markers in aHSCs (77)(78)(79), and IL10-and IL22-induced aHSC death by senescence (80,81).…”

Section: Activation Of Hscs and Liver Fibrosismentioning

confidence: 99%

“…Remarkable advancements have been made in identifying the cell types that co-ordinate fibrogenesis as well as the underlying inter-and intra-cellular signaling mechanisms (6)(7)(8)(9). Several animal models of liver fibrosis of various etiologies have been developed (10,11), and monoand co-culture systems established (8,12,13) to discover the mechanisms of cross-communication amongst the liver resident cells, infiltrating inflammatory cells and immune cells implicated in fibrosis at the organ and cellular/subcellular levels. However, fibrosis of the liver and other organs remains untreatable.…”

Section: Introductionmentioning

confidence: 99%

“…It is generally accepted that activated proliferating hepatic stellate cells (HSCs) are responsible for liver fibrosis regardless of the etiology. An exception to this is biliary injury-induced disease in which portal (myo)fibroblasts are the major cells during initial period and are also significantly involved, along with HSCs, at later times of the disease progression (8,13,14). Inflammation initiated by the hepatocyte damage plays a critical role both in activation and fibrogenic activity of HSCs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation