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LIVER AND BILIARY TRACT

Two populations of Thy1-positive mesenchymal cells regulate in vitro maturation of hepatic progenitor cells

¹Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto; ²Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo; and ³Laboratory of Stem Cell Differentiation, Institute for Frontier Medical Sciences, and ⁴Molecular and Cancer Research Unit, HMRO, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Submitted 2 June 2006 ; accepted in final form 12 September 2006

We previously reported that the in vitro maturation of CD49f⁺Thy1^–CD45^– (CD49f positive) fetal hepatic progenitor cells (HPCs) is supported by Thy1-positive mesenchymal cells derived from the fetal liver. These mesenchymal cell preparations contain two populations, one of a cuboidal shape and the other spindle shaped in morphology. In this study, we determined that the mucin-type transmembrane glycoprotein gp38 could distinguish cuboidal cells from spindle cells by immunocytochemistry. RT-PCR analysis revealed differences between isolated CD49f^±Thy1⁺gp38⁺CD45^– (gp38 positive) cells and CD49f^±Thy1⁺gp38^–CD45^– (gp38 negative) cells, whereas both cells expressed mesenchymal cell markers. The coculture with gp38-positive cells promoted the maturation of CD49f-positive HPCs, which was estimated by positivity for periodic acid-Schiff (PAS) staining, whereas the coculture with gp38-negative cells maintained CD49f-positive HPCs negative for PAS staining. The expression of mature hepatocyte markers, such as tyrosine aminotransferase, tryptophan-2,3-dioxygenase, and glucose-6-phosphatase, were upregulated on HPCs by coculture with gp38-positive cells. Furthermore, transmission electron microscopy revealed the acquisition of mature hepatocyte features by HPCs cocultured with gp38-positive cells. This effect on maturation of HPCs was inhibited by the addition of conditioned medium derived from gp38-negative cells. By contrast, the upregulation of bromodeoxyuridine incorporation by HPCs demonstrated the proliferative effect of coculture with gp38-negative cells. In conclusion, these results suggest that in vitro maturation of HPCs promoted by gp38-positive cells may be opposed by an inhibitory effect of gp38-negative cells, which likely maintain the immature, proliferative state of HPCs.

gp38-positive cells; gp38-negative cells; coculture; immature

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