Wnt/β‐catenin signaling mediates oval cell response in rodents

Adult hepatic stem cells or oval cells are facultative stem cells in the liver that are activated during regeneration only during inhibition of innate hepatocyte proliferation. On the basis of its involvement in liver cancer, regeneration, and development, we investigated the role of the Wnt/β‐catenin pathway in oval cell response, which was initiated in male Fisher rats with 2‐acetylaminofluorine and two‐third partial hepatectomy (PHX). Extensive oval cell activation and proliferation were observed at 5 and 10 days post‐PHX, as indicated by hematoxylin‐eosin and proliferating cell nuclear antigen analysis. A noteworthy increase in total and active β‐catenin was observed at this time, which was localized to the oval cell cytoplasm and nuclei by immunohistochemistry and confirmed by double immunofluorescence. A concomitant increase in Wnt‐1 in hepatocytes along with increased expression of Frizzled‐2 in oval cells was observed. This paracrine mechanism coincided with a decrease in Wnt inhibitory factor‐1 and glycogen synthase kinase‐3β down‐regulation leading to β‐catenin stabilization. To strengthen its role, β‐catenin conditional knockout mice were treated with 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine to induce oval cell activation. A dramatic decrease in the A6‐positive oval cell numbers in the absence of β‐catenin demonstrated a critical role of β‐catenin in oval cell biology. Conclusion: The Wnt/β‐catenin pathway plays a key role in the normal activation and proliferation of adult hepatic stem cells. (HEPATOLOGY 2007.)

[1]  S. Bae,et al.  Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. , 2007, Gastroenterology.

[2]  E. Keller,et al.  The role of Wnts in bone metastases , 2007, Cancer and Metastasis Reviews.

[3]  Sanjeev Gupta,et al.  Novel hepatic progenitor cell surface markers in the adult rat liver , 2007, Hepatology.

[4]  B. Cieply,et al.  Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. , 2006, Gastroenterology.

[5]  J. Sicklick,et al.  Evidence for epithelial-mesenchymal transitions in adult liver cells. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[6]  B. Cieply,et al.  Activation of Wnt/β‐catenin pathway during hepatocyte growth factor–induced hepatomegaly in mice , 2006, Hepatology.

[7]  R. Parks,et al.  Hepatic progenitor cells in human fetal liver express the oval cell marker Thy-1. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[8]  S. Feng,et al.  Liver‐specific loss of β‐catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice , 2006, Hepatology.

[9]  S. Thorgeirsson,et al.  A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells , 2006, Nature Medicine.

[10]  J. Zucman‐Rossi,et al.  Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC , 2006, Hepatology.

[11]  J. Olynyk,et al.  Jekyll and Hyde: evolving perspectives on the function and potential of the adult liver progenitor (oval) cell. , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[12]  A. Bell,et al.  Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. , 2005, Gastroenterology.

[13]  J. Olynyk,et al.  Oncostatin M induces an acute phase response but does not modulate the growth or maturation-status of liver progenitor (oval) cells in culture. , 2005, Experimental cell research.

[14]  C. Guha,et al.  Bone Marrow Progenitors Are Not the Source of Expanding Oval Cells in Injured Liver , 2004, Stem cells.

[15]  Ajamete Kaykas,et al.  WNT and β-catenin signalling: diseases and therapies , 2004, Nature Reviews Genetics.

[16]  M. Lu,et al.  Expression of Frizzled genes in developing and postnatal hair follicles. , 2004, The Journal of investigative dermatology.

[17]  S. Thorgeirsson,et al.  2‐acetylaminofluorene dose‐dependent differentiation of rat oval cells into hepatocytes: Confocal and electron microscopic studies , 2004, Hepatology.

[18]  G. Michalopoulos,et al.  Beta-catenin is temporally regulated during normal liver development. , 2004, Gastroenterology.

[19]  M. Grompe.  The Role of Bone Marrow Stem Cells in Liver Regeneration , 2003, Seminars in liver disease.

[20]  Xin Wang,et al.  The origin and liver repopulating capacity of murine oval cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Moon.  The Wnt/β-catenin Pathway , 2003, Science's STKE.

[22]  E. Scott,et al.  Mouse A6–positive hepatic oval cells also express several hematopoietic stem cell markers , 2003, Hepatology.

[23]  David I. Smith,et al.  Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas , 2002, Oncogene.

[24]  A. Bell,et al.  Hepatocyte Growth Factor Induces Wnt-independent Nuclear Translocation of β-Catenin after Met-β-Catenin Dissociation in Hepatocytes , 2002 .

[25]  G. Yeoh,et al.  Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. , 2002, Carcinogenesis.

[26]  D. Stolz,et al.  Changes in WNT/β‐catenin pathway during regulated growth in rat liver regeneration , 2001 .

[27]  B. Petersen.  Hepatic "stem" cells: coming full circle. , 2001, Blood cells, molecules & diseases.

[28]  S. Thorgeirsson,et al.  Origin and structural evolution of the early proliferating oval cells in rat liver. , 2001, The American journal of pathology.

[29]  J. Lunz,et al.  Concanavalin A simultaneously primes liver hematopoietic and epithelial progenitor cells for parallel expansion during liver regeneration after partial hepatectomy in mice , 2000, Hepatology.

[30]  Sunil Badve,et al.  Derivation of hepatocytes from bone marrow cells in mice after radiation‐induced myeloablation , 2000, Hepatology.

[31]  W. Mars,et al.  Bone marrow as a potential source of hepatic oval cells. , 1999, Science.

[32]  S. Thorgeirsson,et al.  Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[33]  P. van Eyken,et al.  Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. , 1998, Journal of hepatology.

[34]  J. Papkoff,et al.  WNT-1 and HGF Regulate GSK3β Activity and β-Catenin Signaling in Mammary Epithelial Cells , 1998 .

[35]  G. Michalopoulos,et al.  Hepatic oval cells express the hematopoietic stem cell marker thy‐1 in the rat , 1998, Hepatology.

[36]  G. Michalopoulos,et al.  Bile ductular damage induced by methylene dianiline inhibits oval cell activation. , 1997, The American journal of pathology.

[37]  A. Ishizu,et al.  Thy-1 induced on rat endothelium regulates vascular permeability at sites of inflammation. , 1995, International immunology.

[38]  F. Kroese,et al.  Identification and kinetics of two recently bone marrow-derived B cell populations in peripheral lymphoid tissues. , 1995, Cellular immunology.

[39]  D. Opstelten,et al.  In situ visualization of hemopoietic cell subsets and stromal elements in rat and mouse bone marrow by immunostaining of frozen sections. , 1991, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[40]  Randall T Moon,et al.  WNT and beta-catenin signalling: diseases and therapies. , 2004, Nature reviews. Genetics.

[41]  Jean S. Campbell,et al.  The role of hepatocytes and oval cells in liver regeneration and repopulation , 2003, Mechanisms of Development.

[42]  G. Michalopoulos,et al.  Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. , 2003, Gastroenterology.

[43]  A. Bell,et al.  Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. , 2002, Cancer research.

[44]  Jack A. Taylor,et al.  CTNNB1 mutations and β‐catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1 † , 2001, Molecular carcinogenesis.

[45]  D. Stolz,et al.  Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration. , 2001, Hepatology.

[46]  J. Papkoff,et al.  WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells. , 1998, Biochemical and biophysical research communications.