Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice

Nishio, Toshikazu; Hu, Ronglin; Koyama, Yukinori; Liang, Shuang; Rosenthal, Sara Brin; Yamamoto, Gen; Karin, Daniel; Baglieri, Jacopo; Ma, Hsiao-Yen; Xu, Jun; Liu, Xiao; Dhar, Debanjan; Iwaisako, Keiko; Taura, Kojiro; Brenner, David A.; Kisseleva, Tatiana

doi:10.1016/j.jhep.2019.04.012

Cited by 92 publications

(99 citation statements)

References 33 publications

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“…(29) Indeed, it was recently demonstrated that in the multidrug resistance protein 2 knockout (Mdr2 −/− ) mouse, a murine model of sclerosing cholangitis, and other models of cholestatic liver injury, activated PFs and HSCs, but not bone marrow-derived fibrocytes, contribute to liver fibrosis, with activated PFs predominantly localized to the peribiliary area and activated HSCs found within the portal and sinusoidal areas. (27) Abundant DRCs and extensive fibrosis are features of late-stage PSC, as well as older Mdr2 −/− mice, although whether fibrosis precedes and supports the DRC proliferation or DRCs promote the development of fibrosis remains to be clarified. Interestingly, genetic deletion of the receptor for TNF-related apoptosis-inducing ligand (TRAIL) exacerbates the ductular reaction and causes parenchymal, bridging fibrosis in the Mdr2 −/− mouse (Mdr2 −/− Tr −/− ), suggesting that TRAIL proapoptotic signaling may restrain the expansion of DRCs, which, in turn, can influence HSC activation.…”

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

“…In human liver diseases, the magnitude of the DRC population correlates with the severity of fibrosis, implicating a crosstalk between DRCs and profibrogenic cells; however, the question of whether fibrosis is the cause or the result of the activation and expansion of DRCs remains unanswered . In chronic liver diseases such as PSC, the development of liver fibrosis is promoted by collagen type 1–producing myofibroblasts, derived from either PFs, HSCs, or bone marrow–derived fibrocytes . PFs were initially believed to be the major contributors to peribiliary fibrosis, while HSCs contribute to parenchymal fibrosis .…”

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

“…However, both PFs and HSCs have been shown to be the source of myofibroblasts in cholestatic liver injury, with PFs also being able to directly activate HSCs . Indeed, it was recently demonstrated that in the multidrug resistance protein 2 knockout ( Mdr2 −/− ) mouse, a murine model of sclerosing cholangitis, and other models of cholestatic liver injury, activated PFs and HSCs, but not bone marrow–derived fibrocytes, contribute to liver fibrosis, with activated PFs predominantly localized to the peribiliary area and activated HSCs found within the portal and sinusoidal areas . Abundant DRCs and extensive fibrosis are features of late‐stage PSC, as well as older Mdr2 −/− mice, although whether fibrosis precedes and supports the DRC proliferation or DRCs promote the development of fibrosis remains to be clarified.…”

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

“…(14,24,25) In chronic liver diseases such as PSC, the development of liver fibrosis is promoted by collagen type 1producing myofibroblasts, derived from either PFs, HSCs, or bone marrow-derived fibrocytes. (26,27) PFs were initially believed to be the major contributors to peribiliary fibrosis, while HSCs contribute to parenchymal fibrosis. (28) However, both PFs and HSCs have been shown to be the source of myofibroblasts in cholestatic liver injury, with PFs also being able to directly activate HSCs.…”

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

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The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

et al. 2020

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Cholangiocytes are the target of a group of chronic liver diseases termed the “cholangiopathies,” in which cholangiocytes react to exogenous and endogenous insults, leading to disease initiation and progression. In primary sclerosing cholangitis (PSC), the focus of this review, the cholangiocyte response to genetic or environmental insults can lead to a heterogeneous response; that is, a subpopulation acquires a ductular reactive and proliferative phenotype, while another subpopulation undergoes senescence and growth arrest. Both ductular reactive cholangiocytes and senescent cholangiocytes can modify the periductal microenvironment through their ability to secrete various cytokines, chemokines, and growth factors, initiating and perpetuating inflammatory and profibrotic responses. This review discusses the similarities and differences, the interrelationships, and the potential pathogenic roles of these reactive proliferative and senescent cholangiocyte subpopulations in PSC.

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Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

See 2 more Smart Citations

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

et al. 2020

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“…These include capsid serotypes, promoters, vector dosage, routes of injection, and the timing of injection, suggesting the importance of characterizing responses to AAV in the neonatal liver. It is becoming increasingly clear that non-hepatocytes in the liver such as cholangiocytes, endothelial cells, and fibroblasts contribute to normal liver function as well as disease progression [16][17][18][19][20], implying that non-specific infections of non-parenchymal cells may lead to side effects. Conversely, if AAV8 transduces non-parenchymal cells, this may lead to a broader application of AAV8 vectors.…”

Section: Introductionmentioning

confidence: 99%

Adeno-Associated Virus Serotype 8-Mediated Genetic Labeling of Cholangiocytes in the Neonatal Murine Liver

et al. 2020

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Determination of the cellular tropism of viral vectors is imperative for designing precise gene therapy. It has been widely accepted that transduction of hepatocytes using adeno-associated virus serotype 8 (AAV8) is a promising approach to correct inborn errors in neonates, but the type of neonatal hepatic cells transduced by AAV8 has not been thoroughly investigated. To address this question, we used a reporter mouse that carries Cre recombinase (Cre)-inducible yellow fluorescent protein (YFP). Our analysis primarily focused on cholangiocytes, given their pivotal roles in normal liver function and disease. We treated RosaYFP/+ mice at postnatal day 2 (P2) with AAV8-cytomegalovirus (CMV) promoter-Cre and analyzed livers at P10 and P56. The vast majority of HNF4α+ hepatocytes were labeled with YFP at both time points, and 11.6% and 24.4% of CK19+ cholangiocytes were marked at P10 and P56, respectively. We also detected YFP+ cells devoid of hepatocyte and cholangiocyte markers, and a subset of these cells expressed the endothelial and fibroblast marker CD34. Next, we used the hepatocyte-specific thyroxine-binding globulin (TBG) promoter. Surprisingly, AAV8-TBG-Cre marked 6.8% and 30.9% of cholangiocytes at P10 and P56, respectively. These results suggest that AAV8 can be a useful tool for targeting cholangiocytes in neonatal livers.

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Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population

Sharma,

Ghufran,

Aftab

et al. 2024

Journal of Cell Communication and Signaling

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Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF‐β‐TGF‐β receptor‐I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β‐galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.

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Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice

Cited by 92 publications

References 33 publications

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

Adeno-Associated Virus Serotype 8-Mediated Genetic Labeling of Cholangiocytes in the Neonatal Murine Liver

Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population

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