Regenerative medicine for liver diseases : Analysis of the development and differentiation of hepatic oval cells

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We first examined the expression of Oncostatin M(OSM) and OSM-specific receptor(OSM-R) in the liver undergoing regeneration in the 2-acetylaminofluorene/partial hepatectomy(AAF/PH) model. OSM was expressed in both oval cells and Kupffer cells, but OSM-R was exclusively expressed in oval cells. When rat oval cells (OC15-5) were incubated in the conditioned medium of 293T cells expressing rat OSM cDNA, this resulted in suppression of growth, changes in morphology to possess microvilli and large cytoplasm with developed organells, and expression of hepatocyte markers, such as tyrosine amino transferase and tryptophan oxygenase, in OC15-5 cells. These results indicate that OSM is a key mediator for induction of the differentiation of OC15-5 cells into hepatocytes, and suggest that the OSM/OSM-R system plays a pivotal role in the differentiation of oval cells into hepatocytes, thereby promoting liver regeneration.Next, we examined the expression of Dlk in the AAF/PH model. Immunofluoresence staining analysis revealed that Dlk+ cells expressed oval cell markers, cytokeratin 19(CK19) and α-fetoprotein, indicating that Dlk is expressed in oval cells. However, Dl1k+ cells accounted for only about 20% of total CK19+ oval cells. Dlk+ cells were localized more distantly from the portal vein than Dlk- cells, and were adjacent to mature hepatocytes. Furthermore, at day 12 after PH, only 3% of Dlk+ oval cells expressed Ki67, whereas about 13% of total oval cells expressed Ki67, indicating that Dlk+ oval cells are less proliferative than Dlk- oval cells. Taken together, these results demonstrate that Dlk is expressed in a subpopulation of oval cells and that Dlk+ cells represent intermediate cells between Dlk- oval cells and mature hepatocytes.