Analysis of Liver Repair Mechanisms in Alagille Syndrome and Biliary Atresia Reveals a Role for Notch Signaling

Fabris, Luca; Cadamuro, Massimiliano; Guido, Maria; Spirlı̀, Carlo; Fiorotto, Romina; Colledan, M.; Torre, Giuliano; Alberti, Daniele; Sonzogni, Aurelio; Okolicsányi, Lajos; Strazzabosco, Mario

doi:10.2353/ajpath.2007.070073

Cited by 124 publications

(131 citation statements)

References 52 publications

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“…Although mechanisms underlying these events are incompletely understood, biliary specification and/or morphogenesis are under genetic controls. For instance, defects in notch signaling pathways, hepatic transcription factors, and homoebox regulators, have been incriminated as primary genetic abnormalities in biliary specification and morphogenesis [42,43]. It should be noteworthy that our findings do not imply that cell adhesion molecules are causally significant in biliary development.…”

Section: Cell Adhesion and Organ Morphogenesismentioning

confidence: 53%

Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers

et al. 2007

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Purpose Regulated expression of cell adhesion molecules could be critical in the proliferation, sequestration, and maintenance of stem/progenitor cells. Therefore, we determined fetal and adult stage-specific roles of cell adhesion in liver cell compartments. Methods We performed immunostaining for the adhesion molecules, E-cadherin and Ep-CAM, associated proteins, b-catenin and a-actinin, hepatobiliary markers, albumin, a-fetoprotein, and cytokeratin-19, and the proliferation marker, Ki-67. Expression of albumin was verified by in situ mRNA hybridization. Results In the fetal liver, hepatoblasts showed extensive proliferation with wide expression of E-cadherin, b-catenin, and a-actinin, although Ep-CAM was expressed in these cells less intensely and focally in the cell membrane to indicate weak cell adhesion. Hepatoblasts in ductal plate and bile ducts showed less proliferation and Ep-CAM was intensely expressed in these cells throughout the cell membrane, indicating strong adhesion. In some ductal plate cells, b-catenin was additionally in the cytoplasm and nucleus, suggesting active cell signaling by adhesion molecules. In adult livers, cells were no longer proliferating and E-cadherin, b-catenin, and a-actinin were expressed in hepatocytes throughout, whereas Ep-CAM was expressed in only bile duct cells. Some cells in ductal structures of the adult liver with Ep-CAM coexpressed albumin and cytokeratin-19, indicating persistence of fetal-like stem/progenitor cells. Conclusions Regulated expression of Ep-CAM supported proliferation in fetal hepatoblasts through weak adhesion and helped in biliary morphogenesis by promoting stronger adhesion in hepatoblasts during this process. Restriction of Ep-CAM expression to bile ducts in the adult liver presumably facilitated sequestration of stem/progenitor cells. This stage-specific and cell compartment-related regulation of adhesion molecules should be relevant for defining how liver stem/progenitor cells enter, exit, and remain in hepatic niches during both health and disease.

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Section: Cell Adhesion and Organ Morphogenesismentioning

confidence: 53%

Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers

et al. 2007

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“…Consistent with this, the extent of bile duct paucity varies with location in ALGS liver (7,52,53), and is most severe in the liver periphery (56). Based upon analysis of ALGS liver tissue, it has been proposed that altered Notch signaling impairs the formation of the distal branches of the biliary tree during the postnatal period in ALGS liver (57). We propose that the ALGS mutation specifically affects postnatal liver development, because this occurs when the liver precursor cells are no longer in contact with surrounding mesodermal tissue.…”

Section: Discussionmentioning

confidence: 97%

Human hepatic organoids for the analysis of human genetic diseases

Guan¹,

Xu²,

Garfin³

et al. 2017

JCI Insight

184

196

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“…A recent study revealed reduced hepatic fibrosis in patients with Alagille syndrome (AGS), a genetic disorder of Notch signaling, caused by mutations in the genes encoding Jagged1 or Notch2 receptor itself. 52 This was thought to be attributable to an accumulation of intermediate hepatobiliary cells unable to transdifferentiate into biliary cells because of the defective Jagged1/Notch2 signaling, which then proceeds with a form of fibrotic reaction characterized by thin septa and pericellular distribution. However, the effects on myofibroblast differentiation (from hepatic stellate cells) are not studied in these patients.…”

Section: Discussionmentioning

confidence: 99%

Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation

Liu

Choi

et al. 2009

The American Journal of Pathology

112

105

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Notch1 is an evolutionarily conserved receptor that regulates cell fate, including such events as differentiation, proliferation, and apoptosis. Myofibroblast differentiation is a key feature of lung fibrosis. Found in inflammatory zone 1 (FIZZ1) has direct fibrogenic properties because of its ability to induce myofibroblast differentiation. However, the downstream signaling pathway that mediates FIZZ1 induction of myofibroblast differentiation remains unknown. The objective of this study was to investigate the involvement of Notch signaling in FIZZ1 induction of lung myofibroblast differentiation and thus explore the potential role of Notch1 in pulmonary fibrosis. The results showed that FIZZ1 increased the expression levels of activated intracellular domain of Notch1 (NIC), its ligand Jagged1, and its target gene Hes1, which were associated with elevated ␣-smooth muscle actin expression levels. Fibroblast ␣-smooth muscle actin expression is induced by the overexpression of NIC but is suppressed by the inhibition of NIC. Moreover, lung fibroblasts that were isolated from mice lacking the GDP-4-keto-6-deoxymannose3,5-epimerase-4-reductase enzyme (FX knockout) exhibited significantly reduced responsiveness to FIZZ1, which was reversed by fucose supplementation. In the absence of exogenous fucose, these FX-deficient cells exhibited defective fucosylation, which is required for Notch signaling. These knockout mice also showed impaired lung fibrosis. These findings suggest that Notch1 signaling in response to FIZZ1 may play a significant role in myofibroblast differentiation during lung fibrosis.

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Analysis of Liver Repair Mechanisms in Alagille Syndrome and Biliary Atresia Reveals a Role for Notch Signaling

Cited by 124 publications

References 52 publications

Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers

Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers

Human hepatic organoids for the analysis of human genetic diseases

Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation

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