Stem cells, cell transplantation and liver repopulation

Abstract

Liver transplantation is currently the only therapeutic option for patients with end-stage chronic liver disease and for severe acute liver failure. Because of limited donor availability, attention has been focused on the possibility to restore liver mass and function through cell transplantation. Stem cells are a promising source for liver repopulation after cell transplantation, but whether or not the adult mammalian liver contains hepatic stem cells is highly controversial. Part of the problem is that proliferation of mature adult hepatocytes is sufficient to regenerate the liver after two-thirds partial hepatectomy or acute toxic liver injury and participation of stem cells is not required. However, under conditions in which hepatocyte proliferation is blocked, undifferentiated epithelial cells in the periportal areas, called "oval cells", proliferate, differentiate into hepatocytes and restore liver mass. These cells are referred to as facultative liver stem cells, but they do not repopulate the normal liver after their transplantation. In contrast, epithelial cells isolated from the early fetal liver can effectively repopulate the normal liver, but they are already traversing the hepatic lineage and may not be true stem cells. Mesenchymal stem cells and embryonic stem cells can be induced to differentiate along the hepatic lineage in culture, but at present these cells are inefficient in repopulating the liver. This review will characterize these various cell types and compare the properties of these cells and the conditions under which they do or do not repopulate the liver following their transplantation.

Figure 1

Schematic diagram showing the lineage progression of stem cells in the mammalian blastocyst to adult somatic cells in various tissues.

Figure 2

Experimental design used to show repopulation of the rat liver by fetal liver stem/progenitor cells. Cells isolated from wt (DPPIV⁺) ED14 F344 rat liver are transplanted into the liver of adult DPPIV⁻ mutant F344 rats immediately after two-thirds PH and repopulation is followed over time by enzyme histochemistry for DPPIV.

Figure 3

Schematic diagram summarizing the various stem or progenitor-like cells that have been transplanted into rats or mice, producing progeny exhibiting either an hepatocytic or bile ductular phenotype. (FLSPC = fetal liver stem/progenitor cells, HSC = hematopoietic stem cells, MSC = mesenchymal stem cells, ES = embryonic stem)