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First published online 4 March 2008
doi: 10.1242/jcs.019315

Journal of Cell Science 121, 1002-1013 (2008)
Published by The Company of Biologists 2008
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Research Article

Phenotype reversion in fetal human liver epithelial cells identifies the role of an intermediate meso-endodermal stage before hepatic maturation

Mari Inada1,2,3, Antonia Follenzi1,2,4,5, Kang Cheng1,2,6, Manju Surana1,6, Brigid Joseph1,2, Daniel Benten1,2, Sriram Bandi1,2,8, Hong Qian7 and Sanjeev Gupta1,2,4,6,7,8,*

1 Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
2 Marion Bessin Liver Research Center, Ullmann Building 5th and 6th floors, 1300 Morris Park Avenue, Bronx, NY 10461, USA
3 Departments of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Japan
4 Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
5 University of Piemonte Orientale, Novara, Italy
6 Diabetes Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
7 Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
8 Center for Human Embryonic Stem Cell Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

* Author for correspondence (e-mail: sanjvgupta{at}pol.net)

Accepted 21 December 2007

Understanding the biological potential of fetal stem/progenitor cells will help define mechanisms in liver development and homeostasis. We isolated epithelial fetal human liver cells and established phenotype-specific changes in gene expression during continuous culture conditions. Fetal human liver epithelial cells displayed stem cell properties with multilineage gene expression, extensive proliferation and generation of mesenchymal lineage cells, although the initial epithelial phenotype was rapidly supplanted by meso-endodermal phenotype in culture. This meso-endodermal phenotype was genetically regulated through cytokine signaling, including transforming growth factor β, bone morphogenetic protein, fibroblast growth factor and other signaling pathways. Reactivation of HNF3{alpha} (FOXA1) transcription factor, a driver of hepatic specification in the primitive endoderm, indicated that the meso-endodermal phenotype represented an earlier developmental stage of cells. We found that fetal liver epithelial cells formed mature hepatocytes in vivo, including after genetic manipulation using lentiviral vectors, offering convenient assays for analysis of further cell differentiation and fate. Taken together, these studies demonstrate plasticity in fetal liver epithelial stem cells, offer paradigms for defining mechanisms regulating lineage switching in stem cells, and provide potential avenues for regulating cell phenotypes for applications of stem cells, such as for cell therapy.

Key words: Fetal, Epithelial, Liver, Mesenchymal, Stem cells, Differentiation






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