Structural analysis of oval‐cell–mediated liver regeneration in rats

We have analyzed the architectural aspects of progenitor‐cell–driven regenerative growth in rat liver by applying the 2‐acetaminofluorene/partial hepatectomy experimental model. The regeneration is initiated by the proliferation of so‐called oval cells. The oval cells at the proximal tips of the ductules have a more differentiated phenotype and higher proliferative rate. This preferential growth results in the formation of a seemingly random collection of small hepatocytes, called foci. These foci have no clonal origin, but possess a highly organized structure, which shows similarities to normal hepatic parenchyma. Therefore, they can easily remodel into the lobular structure. Eventually, the regenerated liver is constructed by enlarged hepatic lobules; no new lobules are formed during this process. The foci of the Solt‐Farber experimental hepatocarcinogenesis model have identical morphological features; accordingly, they also represent only regenerative, not neoplastic, growth. Conclusion: Progenitor‐cell–driven liver regeneration is a well‐designed, highly organized tissue reaction, and better comprehension of the architectural events may help us to recognize this process and understand its role in physiological and pathological reactions. (HEPATOLOGY 2012)

[1]  F. Lemaigre Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. , 2009, Gastroenterology.

[2]  M. Tatematsu,et al.  Relative merits of immunohistochemical demonstrations of placental, A, B and C forms of glutathione S-transferase and histochemical demonstration of gamma-glutamyl transferase as markers of altered foci during liver carcinogenesis in rats. , 1985, Carcinogenesis.

[3]  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.

[4]  Matthias Hermes,et al.  Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration , 2010, Proceedings of the National Academy of Sciences.

[5]  D. Solt,et al.  New principle for the analysis of chemical carcinogenesis , 1976, Nature.

[6]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[7]  A. Medline,et al.  Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis. , 1977, The American journal of pathology.

[8]  K. Wake,et al.  The portal lobule in rat liver fibrosis: A re‐evaluation of the liver unit , 1998, Hepatology.

[9]  A. West,et al.  Nomenclature of the finer branches of the biliary tree: Canals, ductules, and ductular reactions in human livers , 2004, Hepatology.

[10]  J. Rossant,et al.  Liver Organogenesis Promoted by Endothelial Cells Prior to Vascular Function , 2001, Science.

[11]  D. Shafritz,et al.  Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. , 1993, The American journal of pathology.

[12]  G. Michalopoulos,et al.  Liver Regeneration , 1997, Science.

[13]  M. Alison,et al.  Liver cancer: the role of stem cells , 2005, Cell proliferation.

[14]  K.,et al.  Studies on the proliferation and fate of oval cells in the liver of rats treated with 2-acetylaminofluorene and partial hepatectomy. , 1984, The American journal of pathology.

[15]  S. Sell On the stem cell origin of cancer. , 2010, The American journal of pathology.

[16]  V. Laszlo,et al.  Architectural changes during regenerative and ontogenic liver growth in the rat , 2009, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[17]  S. Thorgeirsson,et al.  In vivo differentiation of rat liver oval cells into hepatocytes. , 1989, Cancer research.

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

[19]  S. Thorgeirsson,et al.  Triiodothyronine accelerates differentiation of rat liver progenitor cells into hepatocytes , 2008, Histochemistry and Cell Biology.

[20]  H. Teutsch Chemomorphology of liver parenchyma. Qualitative histochemical distribution patterns and quantitative sinusoidal profiles of G6Pase, G6PDH and malic enzyme activity and of glycogen content. , 1981, Progress in histochemistry and cytochemistry.

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

[22]  N. Ferry,et al.  Mature hepatocytes are the source of small hepatocyte-like progenitor cells in the retrorsine model of liver injury. , 2004, Journal of hepatology.

[23]  B. Döme,et al.  Development of arterial blood supply in experimental liver metastases. , 2009, The American journal of pathology.

[24]  N. Tygstrup,et al.  Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell–mediated liver regeneration , 2007, Hepatology.

[25]  George K Michalopoulos,et al.  Liver regeneration. , 2005, Advances in biochemical engineering/biotechnology.

[26]  R. Anderson,et al.  Experimental pathology of liver: restoration of liver in white rat following partial surgical removal , 1931 .

[27]  Y. N. Park,et al.  Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans , 2011, Hepatology.

[28]  A. West,et al.  Regeneration of hepatocyte 'buds' in cirrhosis from intrabiliary stem cells. , 2003, Journal of hepatology.

[29]  T. Kodama,et al.  Expression of Dlk/Pref-1 defines a subpopulation in the oval cell compartment of rat liver. , 2004, Gene expression patterns : GEP.

[30]  K. Jungermann,et al.  Predominant periportal expression of the phosphoenolpyruvate carboxykinase and tyrosine aminotransferase genes in rat liver , 1990, Histochemistry.