Human hepatic stem cells from fetal and postnatal donors

Human hepatic stem cells (hHpSCs), which are pluripotent precursors of hepatoblasts and thence of hepatocytic and biliary epithelia, are located in ductal plates in fetal livers and in Canals of Hering in adult livers. They can be isolated by immunoselection for epithelial cell adhesion molecule-pos...

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Published in:The Journal of experimental medicine 2007-08, Vol.204 (8), p.1973-1987
Main Authors: Schmelzer, Eva, Zhang, Lili, Bruce, Andrew, Wauthier, Eliane, Ludlow, John, Yao, Hsin-lei, Moss, Nicholas, Melhem, Alaa, McClelland, Randall, Turner, William, Kulik, Michael, Sherwood, Sonya, Tallheden, Tommi, Cheng, Nancy, Furth, Mark E, Reid, Lola M
Format: Article
Language:English
Subjects:
alpha-Fetoproteins - metabolism
BASIC BIOLOGICAL SCIENCES
Cell Adhesion
Cell Culture Techniques - methods
Cell Membrane - metabolism
Culture Media, Serum-Free - metabolism
Epithelial Cells - cytology
Hematopoietic Stem Cells - metabolism
Hepatocytes - metabolism
Humans
Immunology
Intercellular Adhesion Molecule-1 - metabolism
Leukocyte Common Antigens - biosynthesis
Liver - cytology
Liver - embryology
Liver - metabolism
Mesoderm - metabolism
Research & Experimental Medicine
Signal Transduction
Stem Cells - cytology
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Summary:Human hepatic stem cells (hHpSCs), which are pluripotent precursors of hepatoblasts and thence of hepatocytic and biliary epithelia, are located in ductal plates in fetal livers and in Canals of Hering in adult livers. They can be isolated by immunoselection for epithelial cell adhesion molecule-positive (EpCAM+) cells, and they constitute approximately 0.5-2.5% of liver parenchyma of all donor ages. The self-renewal capacity of hHpSCs is indicated by phenotypic stability after expansion for >150 population doublings in a serum-free, defined medium and with a doubling time of approximately 36 h. Survival and proliferation of hHpSCs require paracrine signaling by hepatic stellate cells and/or angioblasts that coisolate with them. The hHpSCs are approximately 9 microm in diameter, express cytokeratins 8, 18, and 19, CD133/1, telomerase, CD44H, claudin 3, and albumin (weakly). They are negative for alpha-fetoprotein (AFP), intercellular adhesion molecule (ICAM) 1, and for markers of adult liver cells (cytochrome P450s), hemopoietic cells (CD45), and mesenchymal cells (vascular endothelial growth factor receptor and desmin). If transferred to STO feeders, hHpSCs give rise to hepatoblasts, which are recognizable by cordlike colony morphology and up-regulation of AFP, P4503A7, and ICAM1. Transplantation of freshly isolated EpCAM+ cells or of hHpSCs expanded in culture into NOD/SCID mice results in mature liver tissue expressing human-specific proteins. The hHpSCs are candidates for liver cell therapies.
ISSN:0022-1007
1540-9538
1892-1007
DOI:10.1084/jem.20061603