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Keywords:

  • biliary atresia;
  • liver fibrosis;
  • DLK1;
  • cytokine expression array;
  • real-time quantitative reverse transcription-PCR;
  • immunohistochemistry;
  • confocal microscopy;
  • in situ hybridization

Abstract

Advanced liver cirrhosis frequently occurs in infants with biliary atresia despite early surgical correction. The aetiology is unknown, but may involve many cytokines and liver cells including hepatic stellate cells (HSCs). A cytokine expression array and real-time quantitative reverse transcription-polymerase chain reaction (QRT-PCR) were used to study cytokine expression during the progression of liver fibrosis in biliary atresia. A Delta-like 1 homologue (DLK1) gene was identified and this gene was up-regulated during the early stage, and down-regulated during the late stage, of biliary atresia, similar to the expression pattern of the procollagen α1(I) gene. Further characterization with immunohistochemistry, confocal microscopy, and in situ hybridization revealed that the DLK1 protein was mainly present in the cytoplasm of smooth muscle actin-positive mesenchymal cells that were morphologically and immunohistochemically identical to activated HSCs/myofibroblasts, whereas DLK1 mRNA was present only in hepatocytes. As DLK1 is a negative regulator of adipocyte differentiation and may control cell fate during differentiation, overexpression of DLK1 protein in HSCs in the early stage of biliary atresia suggests that DLK1 may be implicated in the transformation of HSCs from fat-storing cells to myofibroblasts and in fibrogenesis associated with biliary atresia. Copyright © 2004 John Wiley & Sons, Ltd.