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TISSUE-SPECIFIC STEM CELLS

Isolation, Characterization, and Differentiation to Hepatocyte-Like Cells of Nonparenchymal Epithelial Cells from Adult Human Liver

^aInstitut National de la Santé et de la Recherche Médicale, Montpellier, France;
^bUniversity of Montpellier, Montpellier, France;
^cService d'Anatomie Pathologique, Hôpital Guy de Chauliac, Montpellier, France;
^dService de Chirurgie Digestive II and
^eService Médico-Chirurgical des Maladies de l'Appareil Digestif et Transplantation Hépatique, Hôpital Saint Eloi, Montpellier, France;
^fService de Chirurgie Digestive, Hôpital Haut Lévèque, Pessac, France

Key Words. Human adult hepatic progenitors • Stem cell • Oval cell • Hepatobiliary cell • Differentiation

Correspondence: Martine Daujat-Chavanieu, Ph.D., INSERM U632, 1919 route de Mende, 34293 Montpellier, France. Telephone: 33-4-67-61-33-61; Fax: 33-4-67-52-36-81; e-mail: daujat{at}montp.inserm.fr

Received October 24, 2006; accepted for publication March 28, 2007.
First published online in STEM CELLS EXPRESS   April 5, 2007.



Activation and proliferation of human liver progenitor cells has been observed during acute and chronic liver diseases. Our goal was to investigate the presence of these putative progenitors in the liver of patients who underwent lobectomy for various reasons but did not show any hepatic insufficiency. Hepatic lesions were evaluated by histological analysis. Nonparenchymal epithelial (NPE) cells were isolated from samples of human liver resections located at a distance from the lesion that motivated the operation and were cultured and characterized. These cells exhibited a marked proliferative potential. They did not express the classic set of stem cell/progenitor markers (Oct-4, Rex-1, -fetoprotein, CD90, c-kit, and CD34) and were faintly positive for albumin. When cultured at confluence in the presence of hepatocyte growth factor and either epidermal growth factor or fibroblast growth factor-4, they entered a differentiation process toward hepatocytes. Their phenotype was quantitatively compared with that of mature human hepatocytes in primary culture. Differentiated NPE cells expressed albumin; 1-antitrypsin; fibrinogen; hepatobiliary markers such as cytokeratins 7, 19, and 8/18; liver-enriched transcription factors; and genes characterized by either a fetal (cytochrome P4503A7 and glutathione S-transferase ) or a mature (tyrosine aminotransferase, tryptophan 2,3-dioxygenase, glutathione S-transferase , and cytochrome P4503A4) expression pattern. NPE cells could be isolated from the liver of several patients, irrespective of the absence or presence of lesions, and differentiated toward hepatocyte-like cells with an intermediate hepatobiliary and mature/immature phenotype. These cells are likely to represent a resident progenitor population of the adult human liver, even in the absence of hepatic failure.

Disclosure of potential conflicts of interest is found at the end of this article.