Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano, Yasuhiro; Nakao, Sachie; Sumiyoshi, Hideaki; Mikami, Koji; Tanno, Yuri; Sueoka, Minako; Kasahara, Daigo; Kimura, Hiroshi; Moro, Tadashi; Kamiya, Akihide; Hozumi, Katsuto; Inagaki, Yutaka

doi:10.1002/hep4.1026

Cited by 33 publications

(40 citation statements)

References 42 publications

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“…HSCs were prepared from wild‐type male mice using the Pronase and collagenase perfusion method . In some experiments, HSCs were purified by fluorescence‐activated cell sorting using vitamin A autofluorescence.…”

Section: Methodsmentioning

confidence: 99%

“…Hematoxylin and eosin (H&E) or sirius red‐Fast Green FCF staining was done using standard protocols . For immunofluorescence staining, tissue sections were subjected to optimal antigen retrieval using Target Retrieval Solution (pH 9.0; Dako, Glostrup, Denmark) for 10 minutes at 110°C in an autoclave.…”

Section: Methodsmentioning

confidence: 99%

“…HSCs were prepared from wild-type male mice using the Pronase and collagenase perfusion method. (11) In some experiments, HSCs were purified by fluorescence-activated cell sorting using vitamin A autofluorescence. Isolated HSCs were seeded in plastic-bottomed tissue culture plates or dishes at a density of 3.5 × 10 4 cells/cm 2 and were cultured using Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and nonessential amino acids.…”

Section: Isolation and Primary Cultures Of Adult Hscsmentioning

confidence: 99%

“…Six-week-old male mice started to receive subcutaneous injections of 1 mL/kg body weight of CCl 4 (FUJIFILM Wako Pure Chemical Corp., Osaka, Japan) every 3 days for a total of 20 times, as reported. (11) Forty-eight hours after the final CCl 4 administration, mice were injected intraperitoneally with 3 × 10 11 viral genomes of each AAV6 vector. Administration of CCl 4 was restarted 24 hours after AAV6 infection and continued for a further 5 times.…”

Section: -Induced Liver Fibrosis and Tcf21 Gene Transfermentioning

confidence: 99%

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A Deactivation Factor of Fibrogenic Hepatic Stellate Cells Induces Regression of Liver Fibrosis in Mice

et al. 2020

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Background and Aims Hepatic stellate cells (HSCs), a key player in the progression of liver fibrosis, are activated by various inflammatory stimuli and converted to myofibroblast‐like cells with excessive collagen production. Despite many attempts to suppress activation of HSCs or inhibit collagen production in activated HSCs, their clinical applications have not been established yet. Recently, the deactivation of HSCs has been reported as a mechanism underlying the reversibility of experimental liver fibrosis. In the present study, we sought for deactivation factors of HSCs that induce regression of established liver fibrosis. Approach and Results We identified transcription factor 21 (Tcf21) as one of the transcription factors whose expression was up‐regulated in parallel to the differentiation of fetal HSCs. Expression of Tcf21 in HSCs remarkably decreased during culture‐induced activation in vitro and in murine and human fibrotic liver tissue in vivo. This reduced Tcf21 expression was recovered during the spontaneous regression of murine liver fibrosis. Tcf21 was also examined for its effects by adeno‐associated virus serotype 6‐mediated Tcf21 gene transfer into cultured activated HSCs and mice with carbon tetrachloride‐ or methionine‐choline deficient diet‐induced liver fibrosis. Overexpression of Tcf21 in activated HSCs not only suppressed fibrogenic gene expression but also restored cells, at least in part, to a quiescent phenotype both in vitro and in vivo. These phenotypic changes of HSCs were accompanied by the regression of steatohepatitis and fibrosis and improved hepatic architecture and function. Conclusions Tcf21 has been identified as a deactivation factor of fibrogenic HSCs, providing insight into a treatment strategy for the otherwise intractable liver fibrosis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Isolation and Primary Cultures Of Adult Hscsmentioning

confidence: 99%

Section: -Induced Liver Fibrosis and Tcf21 Gene Transfermentioning

confidence: 99%

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A Deactivation Factor of Fibrogenic Hepatic Stellate Cells Induces Regression of Liver Fibrosis in Mice

et al. 2020

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“…Consequently, our data clearly show that the αSMA positive PMFs are located in the PVM adjacent to the BECs at E14.5‐E18.5 and PMFs surrounded the bile duct at P0‐P10, suggesting that PMFs may play an important role in IHBDs development. A recently study reported that αSMA positive myofibroblasts in CCL4‐treated livers expressed Jagged1 (Nakano et al, ). Indeed, the IHC results showed that α‐SMA positive cells expressed Jagged1 in the PVM.…”

Section: Discussionmentioning

confidence: 99%

TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1‐Notch‐Sox9 signaling axis

Wang

Feng

Yasen

et al. 2018

Journal Cellular Physiology

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Due to the inherent limitations of the mouse models, the molecular mechanism of TGFβ signaling involved in the development of intrahepatic bile ducts (IHBDs) has been investigated little. Here, we investigated the role of TGFβ signaling and its regulatory mechanism in IHBDs development. We demonstrate that TGFβ signaling pathway activity is essential for IHBDs development. When blocking TGFβ signaling at E10.5, the number of bile ducts in hilum was reduced more than two fold and number of CK19 positive chlangiocytes in periphery was reduced more than 3.5-fold compared with controls. We also show that alpha-smooth muscle actin (α-SMA)-immunoreactive cells are located in the portal vein mesenchyme (PVM) adjacent to the bile ducts during IHBDs development and identify the α-SMA positive cells expressing the Notch ligand Jagged1 in the periportal area. Importantly, after blocking TGFβ signaling, the expression of Jagged1 was selectively decreased in the PVM but not in biliary epithelial cells (BECs), which is associated with the transformation of portal mesenchyme cells (PMCs) into portal myofibroblasts (PMFs). In addition, Sox9, which is downstream of Notch, is decreased after blocking the TGFβ signaling pathway in the liver. Our findings uncover a novel mechanism of TGFβ signaling in controlling the development of IHBDs may through regulating the Jagged1-Notch-Sox9 signaling axis.

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Identification of a Novel Bone Marrow Cell-Derived Accelerator of Fibrotic Liver Regeneration Through Mobilization of Hepatic Progenitor Cells in Mice

et al. 2018

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Granulocyte colony stimulating factor (G-CSF) has been reported to ameliorate impaired liver function in patients with advanced liver diseases through mobilization and proliferation of hepatic progenitor cells (HPCs). However, the underlying mechanisms remain unknown. We previously showed that G-CSF treatment increased the number of bone marrow (BM)-derived cells migrating to the fibrotic liver following repeated carbon tetrachloride (CCl 4 ) injections into mice. In this study, we identified opioid growth factor receptor-like 1 (OGFRL1) as a novel BM cellderived accelerator of fibrotic liver regeneration in response to G-CSF treatment. Endogenous Ogfrl1 was highly expressed in the hematopoietic organs such as the BM and spleen, whereas the liver contained a relatively small amount of Ogfrl1 mRNA. Among the peripheral blood cells, monocytes were the major sources of OGFRL1. Endogenous Ogfrl1 expression in both the peripheral blood monocytes and the liver was decreased following repeated CCl 4 injections. An intrasplenic injection of cells overexpressing OGFRL1 into CCl 4 -treated fibrotic mice increased the number of HPC and stimulated proliferation of hepatic parenchymal cells after partial resection of the fibrotic liver. Furthermore, overexpression of OGFRL1 in cultured HPC accelerated their differentiation as estimated by increased expression of liver-specific genes such as hepatocyte nuclear factor 4α, cytochrome P450, and fatty acid binding protein 1, although it did not affect the colony forming ability of HPC. These results indicate a critical role of OGFRL1 in the mobilization and differentiation of HPC in the fibrotic liver, and administration of OGFRL1-expressing cells may serve as a potential regenerative therapy for advanced liver fibrosis. STEM CELLS 2019; 37:89-101 SIGNIFICANT STATEMENTThe liver is well-known to possess high regenerative capacity in response to injury. However, its regeneration is impaired in the case of advanced liver fibrosis when mature hepatocytes can hardly self-proliferate. Hepatic progenitor cells (HPCs) have been implicated as a source of hepatocytes in regeneration of the fibrotic liver, and efficient mobilization of HPC represents an important strategy to treat liver fibrosis. This study identified a novel blood cell-derived factor that accelerates regeneration of the fibrotic liver through mobilization of HPC. Administration of cells overexpressing this factor may serve as a potential regenerative therapy for advanced liver fibrosis.

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Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Cited by 33 publications

References 42 publications

A Deactivation Factor of Fibrogenic Hepatic Stellate Cells Induces Regression of Liver Fibrosis in Mice

A Deactivation Factor of Fibrogenic Hepatic Stellate Cells Induces Regression of Liver Fibrosis in Mice

TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1‐Notch‐Sox9 signaling axis

Identification of a Novel Bone Marrow Cell-Derived Accelerator of Fibrotic Liver Regeneration Through Mobilization of Hepatic Progenitor Cells in Mice

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