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MBC in Press, published online ahead of print February 21, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0848

A more recent version of this article appeared on April 1, 2007
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Submitted on September 22, 2006
Revised on January 5, 2007
Accepted on February 1, 2007

Liver Progenitor Cells Develop Cholangiocyte-type Epithelial Polarity in Three Dimensional Culture

Naoki Tanimizu,* Atsushi Miyajima,{dagger} and Keith E. Mostov*

*Departments of Anatomy and Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143-2140; {dagger}Institute of Molecular and Cellular Biology, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Monitoring Editor: Asma Nusrat

Cholangiocytes are cellular components of the bile duct system of the liver, which originate from hepatoblasts during embryonic liver development. While several transcription factors and signaling molecules have been implicated in bile duct development, its molecular mechanism has not been studied in detail. Here, we applied a three-dimensional (3D) culture technique to a liver progenitor cell line, HPPL, to establish an in vitro culture system in which HPPL acquire differentiated cholangiocyte characteristics. When HPPL were grown in a gel containing Matrigel, which contains ECM components of basement membrane, HPPL developed apico-basal polarity and formed cysts, which had luminal space inside. In the cysts, F-actin bundles and atypical protein kinase C were at the apical membrane, E-cadherin was localized at the lateral, and {beta}-catenin and integrin {alpha}6 were at the basolateral membrane. HPPL in cysts expressed cholangiocyte markers including cytokeratin 19, integrin {beta}4, and aquaporin-1, but not a hepatocyte marker, albumin. Furthermore, HPPL transported rhodamine 123, a substrate for multi-drug resistance gene products, from the basal side to the central lumen. These data indicate that HPPL develop cholangiocyte-type epithelial polarity in 3D culture. Phosphatidylinositol 3-kinase (PI3K) signaling was essential for proliferation and survival of HPPL in culture, whereas laminin-1 was a crucial component of Matrigel for inducing epithelial polarization of HPPL. Because HPPL cysts display structural and functional similarities with bile ducts, the 3D culture of HPPL recapitulates in vivo cholangiocyte differentiation and is useful to study the molecular mechanism of bile duct development in vitro.

Address correspondence to: Keith E. Mostov (keith.mostov{at}ucsf.edu)




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