**Section 1**

**Cellular and Molecular Mechanisms of Regeneration** 

**1** 

*Italy* 

**Hepatocytes and Progenitor –** 

*Dept. Cellular Biotechnology and Hematology,* 

*"Sapienza" University of Rome,* 

**Stem Cells in Regeneration and Therapy** 

Laura Amicone, Franca Citarella, Marco Tripodi and Carla Cicchini

The liver is a highly specialized detoxifying organ involved in: i) glucose homeostasis; ii) lipid homeostasis and ketone bodies production; iii) metabolism of amino acids. Most of the liver functions are carried out by the hepatocytes (about 70-75% of hepatic cells) that, together with cholangiocytes (10-5 % of hepatic cells), are of endodermal derivation and

The liver has a peculiar and fascinating ability: it is able to regenerate itself after loss of parenchyma for surgical resection or injuries caused by drugs, toxins or acute viral diseases. The ancient myth of Prometheus highlighted this capability: the Titan Prometheus was bound for ever to a rock as punishment by Zeus for his theft of the fire; each day a great eagle ate his liver and each night the liver was regenerated, only to be eaten again the next

The liver compensatory regeneration is a rapid and tightly orchestrated phenomenon efficiently ensuring the reacquisition of the original tissue mass and its functionality. Primarily, it involves the re-entry into cell cycle of parenchymal hepatocytes which are able to completely recover the original liver mass (Fausto, 2000). The liver anatomical and functional units reconstitution also requires non-parenchymal cells (endothelial cells, cholangiocytes, Kupffer cells, stellate cells). It is yet not clear if each cell histotype is involved in the proliferative process or if the regeneration requires the activity of a cell with multiple differentiation potential. Recently, the bipotentiality of the hepatocytes, able to divide giving rise to both hepatocytes and cholangiocytes, has been suggested. Furthermore, when injury is severe or the hepatocytes can no longer proliferate a progenitor cell population, normally a quiescent compartment is activated. A population of small portal cells named oval cells was first identified in 1978 by Shinozuka and colleagues (Shinozuka et al., 1978). Now as "oval cells" is indicated a heterogeneous population of bipotent transient amplifying cells, originating from the Canal of Hering (Dabeva & Shafritz, 1993). These cells are normally quiescent but, after injury, rapidly and extensively proliferate and differentiate

The observation that oval cells are a mixed precursor population suggests their differentiation from liver stem cells (Theise et al., 1999). Since the hepatocytes are able to

**1. Introduction** 

day.

constitute the hepatic parenchyma.

in hepatocytes and cholangiocytes (Yovchev et al., 2008).
