Eva Schmelzer

*McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh, Pennsylvania, USA* 

### **1. Introduction**

42 Liver Regeneration

Yao, Z. & Mishra, L. (2009). Cancer stem cells and hepatocellular carcinoma. *Cancer Biology* 

Yokoyama, S., Sells, M. A., Reddy, T. V. & Lombardi, B. (1985). Hepatocarcinogenic and

Yoon, S. M., Gerasimidou, D., Kuwahara, R., Hytiroglou, P., Yoo, J. E., Park, Y. N. & Theise,

Zhang, A., London, R., Schulz, F. M., Giguere-Simmonds, P. W., Delriviere, L.,

oval cells into hepatocytes. *Experimental Cell Research,* 213, 37-42.

derived from stem/progenitor cells in humans. *Hepatology,* 53, 964-973. You, H., Ding, W. & Rountree, C. B. (2010). Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. *Hepatology,* 51, 1635-1644. Zajicek, G., Oren, R. & Weinreb, M., Jr. (1985). The streaming liver. *Liver,* 5, 293-300.

8078-8083.

2842.

*& Therapy,* 8, 1691-1698.

hormone-producing cells. *Proceedings of the National Academy of Sciences U S A,* 99,

promoting action of a choline-devoid diet in the rat. *Cancer Research,* 45, 2834-

N. D. (2011). Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly

Chandraratana, H., Hardy, K., Zheng, S., Olynyk, J. K. & Yeoh, G. (2010). Human liver progenitor cell lines are readily established from non-tumorous tissue adjacent to hepatocellular carcinoma. *Stem Cells and Development,* 19, 1277-1284. Zhang, M. & Thorgeirsson, S. S. (1994). Modulation of connexins during differentiation of

The liver has a tremendous capacity to regenerate at all developmental stages (for reviews, see (1-3)). Liver cell mass can be restored even after repeated partial hepatectomies as well as after toxic injury. The contribution of stem cells to these processes is still under debate. Adult liver cells have been shown to regenerate liver tissue repeatedly when transplanted serially (4). However, hepatocytes cannot be considered stem cells because they are unipotent (for a glossary of terms, see **Table 1**). This chapter describes various liver progenitors that have been found by different researchers in humans and other mammalian species. Intra and extra-hepatic progenitors are discussed that can give rise to liver lineages. Intra-hepatic progenitors of non-hepatic lineages, such as endothelial or hematopoietic restricted progenitors, are not discussed. Although the focus of this chapter is on progenitors that have been characterized in normal, non-pathological conditions of the liver, oval cells will be described briefly.


Hepatic Progenitors of the Liver and Extra-Hepatic Tissues 45

**Isolation method** 

Culture Positive: CD90, CD73, CD29, CD44, CD13, HLA-class I. Weak: CD49e, CD49b, CD49f. Negative: CD105, CD133, CD117, CD45, CD34, HLA-DR

Culture Positive: CD34, CD90, CD117, CD326, c-met, SSEA4, CK18, CK19, CD44h, vimentin. Negative: CD133, CD45, AFP, albumin

Culture Positive:

MACS, culture

Albumin, AFP, CD29, CD73, CD44, CD90, vimentin, nestin. Weak: CK8, CK18. Negative: CD34, CD45, CD117, CD133, CK19.

Positive: CD326, CD133, CD56, Ecadherin, CD29, CD44h, claudin3, CK19. Weak: albumin. Negative: AFP.

Culture Positive: AFP, GGT, CK8, CK19, CD34

**Phenotype** *In vivo*

**model for repopulation** 

uPA+/+- SCID with and without 70% hepatectomy

Rag2- /- γ- /-

retrorsine/ CCl4

SCID, Nacetyl-paminophen *In vitro*  **characteristics**

Hepatic functions after induced differentiation

Long-term culture, ~46h PDT, multipotent

Multipotent, high expansion potential, ~36h

PDT

NOD/SCID Long-term

SCID CCl4 Long-term culture

culture, >150 population doublings, precursors of hepatoblasts

**Term used by authors** 

Adult derived human liver stem/ progenitor cell (ADHLSCs)

Human fetal liver multipotent progenitor cells (hFLMPC)

stem cells (HLSCs)

Human hepatic stem cells (hHpSC)

liver progenitor/ stem cells

**Publication Develop-**

Najimi *et al*. 2007 (20), Khuu *et al*. 2011 (21)

Dan *et al.* 2006 (19)

Herrera *et al*. 2006 (22)

Schmelzer *et al*. 2006, 2007 (12, 18)

Malhi *et al*. 2002 (23)

Fetal (16-20 weeks of gestation), neonatal, pediatric, adult

**mental stage of liver tissue** 

Adult

Fetal

**Presumable lineage** 

Mesenchymal

Mesendodermal

Endodermal

Fetal Human fetal

Adult Human liver


Table 1. Common terminology relevant to liver progenitor biology. Further details can be found also in (5, 6).
