The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
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Published online
doi:10.1084/jem.20061603
The Journal of Experimental Medicine, Vol. 204, No. 8, 1973-1987
The Rockefeller University Press, 0022-1007 $30.00
© Schmelzer et al.
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ARTICLE

 Human hepatic stem cells from fetal and postnatal donors

Eva Schmelzer1, Lili Zhang1, Andrew Bruce4, Eliane Wauthier1, John Ludlow4, Hsin-lei Yao1,2, Nicholas Moss1, Alaa Melhem1, Randall McClelland1, William Turner1,2, Michael Kulik4, Sonya Sherwood4, Tommi Tallheden1, Nancy Cheng1, Mark E. Furth5, and Lola M. Reid1,2,3

1 Departments of Cell and Molecular Physiology and 2 Biomedical Engineering, 3 Program in Molecular Biology and Biotechnology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599
4 Vesta Therapeutics, Durham, NC 27713
5 Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC 27157

CORRESPONDENCE L.M. Reid:lmreid{at}email.unc.edu

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 ~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 ~36 h. Survival and proliferation of hHpSCs require paracrine signaling by hepatic stellate cells and/or angioblasts that coisolate with them. The hHpSCs are ~9 µm 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.

Abbreviations used: AFP, {alpha}-fetoprotein; CK, cytokeratin; EpCAM, epithelial cell adhesion molecule; hHpSC, human hepatic stem cell; ICAM, intercellular adhesion molecule; KM, Kubota's Medium; NCAM, neural cell adhesion molecule; VEGFr, vascular endothelial growth factor receptor.

E. Schmelzer, L. Zhang, and A. Bruce are co–first authors; and M.E. Furth and L. M. Reid are co–senior authors.

L. Zhang's present address is The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China, 210029.


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