Liver Regeneration in Rats with Retrorsine-Induced Hepatocellular Injury Proceeds through a Novel Cellular Response

Abstract

The adult rodent liver contains at least two recognized populations of cells with stem-like properties that contribute to liver repair/regeneration under different pathophysiological circumstances: (i) unipotential committed progenitor cells (differentiated hepatocytes and biliary epithelial cells) and (ii) multipotential nonparenchymal progenitor cells (oval cells). In retrorsine-induced hepatocellular injury the capacity of fully differentiated rat hepatocytes to replicate is severely impaired and massive proliferation of oval cells does not occur. Nevertheless, retrorsine-exposed rats can replace their entire liver mass after 2/3 surgical partial hepatectomy through the emergence and expansion of a population of small hepatocyte-like progenitor cells that expresses phenotypic characteristics of fetal hepatoblasts, oval cells, and fully differentiated hepatocytes, but differ distinctly from each type of cell. The activation, proliferation, and complete regeneration of normal liver structure from small hepatocyte-like progenitor cells have not been recognized in other models of liver injury characterized by impaired hepatocyte replication. We suggest that the selective emergence and expansion of small hepatocyte-like progenitor cells observed in the retrorsine model reflect a novel mechanism of complete liver regeneration in the adult rat. Furthermore, we suggest that these cells may represent a novel progenitor cell population that (i) responds to liver deficit when the replication capacity of differentiated hepatocytes is impaired, (ii) expresses an extensive proliferative capacity, (iii) can give rise to large numbers of progeny hepatocytes, and (iv) can restore tissue mass.

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…This figure might be even higher if not all the cells that migrated to the liver actually took part in repopulation, and the authors suggested that there might be a sub-population of hepatocyte stem cells designated as 'regenerative transplantable hepatocytes' (RTHs). We could speculate that perhaps these RTHs are analogous to the small hepatocyte-like progenitors (SHPCs) described by Gordon [22]? If rats are pretreated with retrorsine, a pyrrolizidine alkaloid metabolized by the hepatocyte's cytochrome P450 system to metabolites that form DNA adducts, then after a two-thirds PH, regeneration is accomplished by the activation, expansion and differentiation of these so-called SHPCs.…”

Attributes of adult stem cells

“…When rats are treated with retrorsine, this compound is metabolized by the hepatocyte's cytochrome P450 (CYP) mixed function oxidase system to a compound that forms DNA adducts, blocking the cell's ability to proliferate; then, the response to PH regeneration is activation, expansion and differentiation of so-called 'small hepatocyte-like' progenitors (SHPCs) [107]. These cell clusters lack CYP enzymes that are usually readily induced by retrorsine, and this probably accounts for their resistance to the anti-proliferative effects of retrorsine.…”

Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors

“…Stem cells capable of reconstituting the tissues in which they reside include myosatellite cells in skeletal muscle (Grounds, 1999), chondroblasts in the perichondrium surrounding cartilage (Yotsuyanagi et al, 1999), oval cells in the liver (Gordon et al, 2000), preductal stem cells in the pancreas (Bonner-Wier et al, 2000;Ramiya et al, 2000), basal stem cells of epithelial tissues (Slack, 2000), and neuronal stem cells in the brain (Gage, 2000). By contrast, other studies have shown that stem cells residing in one tissue can differentiate into cell types of another tissue.…”