Hepatic progenitor cells in human liver diseases

Libbrecht, Louis; Roskams, Tania

doi:10.1016/s1084952102001258

Cited by 174 publications

(171 citation statements)

References 54 publications

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“…In contrast, the cholangiocytes expressed some markers of mature bile duct cells, such as aquaporin (AQP)-1 40 and cytokeratin (CK)-19, 41,42 but not albumin. Notably, however, under our culture conditions, these cholangiocytes also expressed several markers of immature bile ductular cells, including neural markers (eg, NCAM), 43 muscle pyruvate kinase (mpk), 44 and c-kit. 45 The latter transcripts were also demonstrated in oval cells, which are known to coexpress neural, smooth muscle and progenitor markers.…”

Section: Hh Signaling Increases After Bile Duct Ligationmentioning

confidence: 84%

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Omenetti

Yang

et al. 2007

Laboratory Investigation

163

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In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocytes suggests that mesenchymal-epithelial crosstalk promotes the fibroproliferative response to cholestatic liver injury. Studying BDL mice, we found that bile duct obstruction induces activity of the Hedgehog (Hh) pathway, a system that regulates the viability and differentiation of various progenitors during embryogenesis. After BDL, many bile ductular cells and fibroblastic-appearing cells in the portal stroma express Hh ligands, receptor and/or target genes. Transwell cocultures of an immature cholangiocyte line that expresses the Hh receptor, Patched (Ptc), with liver myofibroblastic cells demonstrated that both cell types produced Hh ligands that enhanced each other's viability and proliferation. Further support for the concept that Hh signaling modulates the response to BDL was generated by studying PtcLacZ mice, which have an impaired ability to constrain Hh signaling due to a heterozygous deficiency of Ptc. After BDL, PtcLacZ mice upregulated fibrosis gene expression earlier than wild-type controls and manifested an unusually intense ductular reaction, more expanded fibrotic portal areas, and a greater number of lobular necrotic foci. Our findings reveal that adult livers resurrect developmental signaling systems, such as the Hh pathway, to guide remodeling of the biliary epithelia and stroma after cholestatic injury.

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Section: Hh Signaling Increases After Bile Duct Ligationmentioning

confidence: 84%

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Omenetti

Yang

et al. 2007

Laboratory Investigation

163

226

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“…This ductular reaction distorts the normal hepatic architecture and causes some degree of hepatic dysfunction, increasing the risk for liver-related mortality, at least in the short-term. On the other hand, because the ductular reaction expands progenitor populations that ultimately generate "fresh" hepatocytes to replace senescent and damaged cells, 8,52 Hh signaling also plays a pivotal role in liver repair. Successful reconstitution of normal hepatic structure/ function will likely necessitate eventual down-regulation of Hh signaling, however, because excessive Hh pathway activity causes dysmorphogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 These findings support the concept that the ductular reaction represents an expansion of the progeny of typically inconspicuous liver progenitors that reside along Canals of Hering in healthy adult livers and suggest that the ductular reaction is involved in liver repair. 8 Fortunately, knowledge about the mechanisms that regulate the ductular response to liver injury is growing [9][10][11][12][13] because such information might suggest novel therapeutic targets to reduce fibrosis and improve regeneration in individuals with alcoholinduced liver injury.…”

mentioning

confidence: 99%

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

et al. 2008

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“…2F and 4A-B) that were recognized on the basis of their morphology and immunohistochemical phenotype. 12 Hepatic progenitor cells were present both in the center and at the edge of the nodules. Reactive bile ductules containing human cells were not observed.…”

Section: Histological Studies Of Uninfected Chimeric Liversmentioning

confidence: 98%

Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera

et al. 2005

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D espite decades of research, the processes that govern liver development and regeneration are only partially understood. A good understanding of the mechanisms that play a role in these processes is important because it may lead to new treatments of human liver diseases. Several in vivo experimental conditions have been used to study liver regeneration and repair and the interaction of different cell types in these processes. These include partial hepatectomy, administration of toxic compounds, or a combination of both, and transgenic expression of certain proteins. 1,2 In contrast to in vitro experiments, these approaches raise fewer questions concerning the influence of artificial matrices on the function and behavior of hepatocytes and other liver cell types.Although these procedures have generated useful information on rodent liver regeneration, stem cell activation, and other processes, extrapolating these findings to the Abbreviations: uPA, urokinase plasminogen activator; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; PAS, periodic-acid-Schiff. From the

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Hepatic progenitor cells in human liver diseases

Cited by 174 publications

References 54 publications

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera

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