Identification of a Bipotential Precursor Cell in Hepatic Cell Lines Derived from Transgenic Mice Expressing Cyto-Met in the Liver

Spagnoli, Francesca M.; Amicone, Laura; Tripodi, Marco; Weiss, Mary C.

doi:10.1083/jcb.143.4.1101

Cited by 77 publications

(79 citation statements)

References 53 publications

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“…There is obvious diversity in the differentiation responses elicited by the various FGFs in different experimental models: in vitro, aFGF promotes hepatocytic differentiation in an established cell line of murine bipotent hepatoblasts (Spagnoli et al 1998); bFGF and FGF7 promote biliary differentiation of chick liver buds in vitro (this report); and FGF10 promotes proliferation in the developing mouse liver (Berg et al, 2007). What causes this diversity of differentiation responses?…”

Section: Fgf Signaling Promotes Bile Duct Differentiation Of the Hepamentioning

confidence: 98%

FGF signaling segregates biliary cell‐lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro

Yanai

Tatsumi

Hasunuma

et al. 2008

Developmental Dynamics

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Intrahepatic bile ducts (IHBDs) are indispensable for transporting bile secreted from hepatocytes to the hepatic duct. The biliary epithelial cells (BECs) of the IHBD arise from bipotent hepatoblasts around the portal vein, suggesting the portal mesenchyme is essential for their development. However, except for Notch or Activin/ TGF-␤ signaling molecules, it is not known which molecules regulate IHBD development. Here, we found that FGF receptors and BMP4 are specifically expressed in the developing IHBD and the hepatic mesenchyme, respectively. Using a mesenchyme-free culture of liver bud, we showed that bFGF and FGF7 induce the hepatoblasts to differentiate into BECs, and that BMP4 enhances bFGF-induced BEC differentiation. The extracellular matrix (ECM) components in the hepatic mesenchyme induced BEC differentiation. Forced expression of a constitutively active form of the FGF receptor partially induced BEC differentiation markers in vivo. These data strongly suggest that bFGF and FGF7 promote BEC differentiation cooperatively with BMP4 and ECMs in vivo.

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Section: Fgf Signaling Promotes Bile Duct Differentiation Of the Hepamentioning

confidence: 98%

FGF signaling segregates biliary cell‐lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro

Yanai

Tatsumi

Hasunuma

et al. 2008

Developmental Dynamics

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“…To determine whether the ES-derived hepatic progenitor cells can differentiate into bile duct cells, they were cultured in Matrigel, previously shown to favor bile duct cell differentiation [Spagnoli et al, 1998;Suzuki et al, 2002]. The cells underwent morphological changes and their proliferation was reduced.…”

Section: In Vitro Differentiation Of Es-derived Hepatic Progenitor Cementioning

confidence: 99%

In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate

Zhou

Xiang

Shao

et al. 2006

J of Cellular Biochemistry

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Recently it was shown that embryonic stem (ES) cells could differentiate into hepatocytes both in vitro and in vivo, however, prospective hepatic progenitor cells have not yet been isolated and characterized from ES cells. Here we presented a novel 4-step procedure for the differentiation of mouse ES cells into hepatic progenitor cells and then hepatocytes. The differentiated hepatocytes were identified by morphological, biochemical, and functional analyses. The hepatic progenitor cells were isolated from the cultures after the withdrawal of sodium butyrate, which was characterized by scant cytoplasm, ovoid nuclei, the ability of rapid proliferation, expression of a series of hepatic progenitor cell markers, and the potential of differentiation into hepatocytes and bile duct-like cells under the proper conditions that favor hepatocyte and bile epithelial differentiation. The differentiation of hepatocytes from hepatic progenitor cells was characterized by a number of hepatic cell markers including albumin secretion, upregulated transcription of glucose-6-phophatase and tyrosine aminotransferase, and functional phenotypes such as glycogen storage. The results from our experiments demonstrated that ES cells could differentiate into a novel bipotential hepatic progenitor cell and mature into hepatocytes with typical morphological, phenotypic and functional characteristics, which provides an useful model for the studies of key events during early liver development and a potential source of transplantable cells for cell-replacement therapies.

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“…Immortalized Met murine hepatocytes (MMH-D3, Amicone et al, 1997;Spagnoli et al, 1998) were grown in RPMI 1640 plus 10% foetal calf serum (FCS), 40 ng/ml recombinant human TGF-a (Sigma, St Louis, USA), 30 ng/ml recombinant human insulin-like growth factor II (IGF-I, Sigma, St Louis, USA), 1.4 nm insulin (Sigma, St Louis, USA) and antibiotics as described previously. MMH-R cells expressing oncogenic vHa-Ras and GFP were cultured as outlined recently (Gotzmann et al, 2002).…”

Section: Cell Culturementioning

confidence: 99%

The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

et al. 2003

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Hepatocytes adopt an invasive and metastatic phenotype caused by the cooperation of transforming growth factor (TGF)-b and oncogenic Ha-Ras. In the initial phase of this process, c-Fos is rapidly induced by TGF-b, but then decreases to undetectable levels. Here, we investigated the functional implications of c-Fos activation and its contribution to hepatocellular tumorigenesis. By employing conditional c-Fos expression, we observed that continuous activation of c-Fos and consequently AP-1 activity leads to depolarization of differentiated murine epithelial hepatocytes. Most remarkably, this change in morphology was associated with inhibition of proliferation and induction of cell death. Coexpression of antiapoptotic Bcl-X L or scavenging of reactive oxygen species was sufficient to prevent the c-Fos-mediated phenotype. In contrast, the cooperation of c-Fos with oncogenic Ha-Ras or a Ras mutant selectively activating the MAPK pathway even enhanced c-Fos-induced effects. Showing the negative role in hepatocellular tumorigenesis, c-Fos repressed oncogenic Ras-driven anchorage-independent growth in vitro and strongly suppressed tumour formation in vivo. Taken together, we demonstrate that c-Fos modulates plasticity of epithelial hepatocytes and acts tumour suppressive in neoplastic hepatocytes by stimulating cell cycle inhibition and cell death.

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Identification of a Bipotential Precursor Cell in Hepatic Cell Lines Derived from Transgenic Mice Expressing Cyto-Met in the Liver

Cited by 77 publications

References 53 publications

FGF signaling segregates biliary cell‐lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro

FGF signaling segregates biliary cell‐lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro

In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate

The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

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