Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma

Terada, Maiko; Horisawa, Kenichi; Miura, Shizuka; Takashima, Yasuo; Ohkawa, Yasuyuki; Sekiya, Sayaka; Matsuda-Ito, Kanae; Suzuki, Atsushi

doi:10.1038/srep34691

Cited by 25 publications

(17 citation statements)

References 43 publications

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“…Malato Y. et al found newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and acute injury; further, conversion of hepatocytes into BECs was not found in commonly used models of biliary injury 10 . Previous studies and our study demonstrated that hepatocytes undergo reversible ductal metaplasia in response to chronic injury 39,40 , expand and subsequently redifferentiate into functional hepatocytes 17 . The difference between Malato Y.…”

Section: Discussionsupporting

confidence: 68%

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin–ɑvβ6 integrin in liver fibrosis

Xiao

et al. 2020

Cell Death Dis

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Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvβ6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvβ6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.

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Section: Discussionsupporting

confidence: 68%

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin–ɑvβ6 integrin in liver fibrosis

Xiao

et al. 2020

Cell Death Dis

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“…Meanwhile, the limitation of use of an Mx‐Cre recombination that induces Jagged1 deletion in a non‐cell type‐specific manner has to be carefully considered. A recent study has implicated Jagged1 expression in macrophages,39 and the lack of Jagged1 expression in many types of cells, including immune cells, may have influenced the results obtained in the present study. Work is in progress in our laboratory to establish a myofibroblast‐specific model of Jagged1 deletion.…”

Section: Discussionmentioning

confidence: 75%

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

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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“…In a mouse model of thioacetamide (TAA)-induced intrahepatic cholangiocarcinoma, KCs accumulate around the central vein area and express Notch ligand Jagged-1 rapidly after the initiation of the TAA treatment, coinciding with the activation of Notch signaling in pericentral hepatocytes. Depletion of KCs prevents the Notch-mediated hepatocytes transformation to cholangiocytes, suggesting that KCs contribute to the cell fate change in hepatocytes (109). Another study has also demonstrated that KCs are required for the proliferation of liver progenitor cells that can differentiate into hepatocytes in a model of cholinedeficient, ethionine-supplemented diet-mediated liver injury and regeneration (110).…”

Section: Crosstalk Between Hepatic Macrophages and Hepatocytesmentioning

confidence: 99%

Hepatic Macrophages in Liver Injury

Shan

2020

Front. Immunol.

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Ample evidence suggests that hepatic macrophages play key roles in the injury and repair mechanisms during liver disease progression. There are two major populations of hepatic macrophages: the liver resident Kupffer cells and the monocyte-derived macrophages, which rapidly infiltrate the liver during injury. Under different disease conditions, the tissue microenvironmental cues of the liver critically influence the phenotypes and functions of hepatic macrophages. Furthermore, hepatic macrophages interact with multiple cells types in the liver, such as hepatocytes, neutrophils, endothelial cells, and platelets. These crosstalk interactions are of paramount importance in regulating the extents of liver injury, repair, and ultimately liver disease progression. In this review, we summarize the novel findings highlighting the impact of injury-induced microenvironmental signals that determine the phenotype and function of hepatic macrophages. Moreover, we discuss the role of hepatic macrophages in homeostasis and pathological conditions through crosstalk interactions with other cells of the liver.

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Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma

Cited by 25 publications

References 43 publications

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin–ɑvβ6 integrin in liver fibrosis

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin–ɑvβ6 integrin in liver fibrosis

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

Hepatic Macrophages in Liver Injury

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