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First published online 30 November 2004
doi: 10.1242/jcs.01572

This Article Figures Only Full Text Full Text (PDF) An erratum has been published All Versions of this Article: jcs.01572v1 117/26/6425    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanimizu, N. Articles by Miyajima, A. Search for Related Content PubMed PubMed Citation Articles by Tanimizu, N. Articles by Miyajima, A.

Long-term culture of hepatic progenitors derived from mouse Dlk⁺ hepatoblasts

¹ Stem Cell Regulation, Kanagawa Academy of Science and Technology (KAST), Teikyo University Biotechnology Research Center, 907 Nogawa, Kawasaki, Kanagawa 216-0001, Japan
² Department of Anatomy, Department of Biochemistry and Biophysics, University of California San Francisco, 600 16th street, San Francisco, CA 94143, USA
³ Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
⁴ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, 332-0012, Japan

^* Author for correspondence (e-mail: miyajima{at}ims.u-tokyo.ac.jp)

Accepted 30 September 2004

We previously demonstrated that hepatoblasts can be isolated from mouse fetal liver based on the expression of delta-like leucine zipper kinase (Dlk), also known as Pref-1. Each Dlk⁺ hepatoblast forms a colony containing both albumin⁺ hepatocytes and cytokeratin 19⁺ (CK19) cholangiocytic cells on either type IV collagen or laminin. Here we show that extracellular matrices (ECMs) significantly affect the growth of Dlk⁺ cells. Dlk⁺ cells vigorously proliferated on type IV collagen-coated dishes in the presence of EGF and HGF during the first 5 days, but their proliferative capability declined thereafter. Dlk⁺ cells also proliferated on laminin-coated plates and some colonies continued to expand even beyond one month after plating. These hepatic progenitor cells proliferating on laminin (HPPL) efficiently proliferated even after replating. Moreover, they were induced to differentiate into hepatocytes and cholangiocytes by overlaying Engelbreth-Holm-Swarm sarcoma (EHS) gel and by embedding in type I collagen gel, respectively. HPPL acquired the metabolic functions of accumulating polysaccharides and detoxifying ammonium ions after hepatic differentiation. Surprisingly, HPPL expressed pancreatic genes such as Pdx1 when dexamethasone was depleted from the culture medium. Therefore, the long-term culture of hepatoblasts on laminin produces multi-potential hepatic progenitors, which possess a strong proliferative capability, differentiate into both hepatocytes and cholangiocytes, and potentially give rise to pancreatic cells.

Key words: Dlk, Laminin, Type IV collagen, Hepatocyte, Cholangiocyte

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