Heterogeneity and plasticity of hepatocyte lineage cells

Abstract

It is hypothesized that the liver has 3 levels of cells in the hepatic lineage that respond to injury or carcinogenesis: 1) the mature hepatocyte, which responds to partial hepatectomy (PH), to centrolobular injury, such as that induced by carbon tetrachloride (CCl 4 ), and to dimethylnitrosamine (DEN) hepatocarcinogenesis; 2) the ductular "bipolar" progenitor cell, which responds to centrolobular injury when the proliferation of hepatocytes is inhibited, and to N-2-acetylaminofluorene (AAF) hepatocarcinogenesis; and 3) the putative periductular stem cell, which responds to periportal injury, such as induced by allyl alcohol and to choline-deficiency models of hepatocarcinogenesis. Hepatocytes are numerous, respond rapidly by 1 or 2 cell cycles, but can only produce other hepatocytes. The ductular progenitor cells are less numerous, may proliferate for longer times than hepatocytes, and are generally considered "bipolar," i. The restitutive response of the liver to different injuries involves proliferation of cells at different levels in the liver lineage. The hypothesis presented by this review is that, similar to other organ systems, the cellular lineage of the liver consists of stem cells, precursor cells (transit-amplifying cells), and mature cells. It is also proposed that there are 2 origins of stem cells in the liver: endogenous and exogenous. 1

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

“…Thus, discrepancies in detecting both Thy1 and AFP in hepatic progenitors may arise from differences in the type of treatment as well as time of phenotypic analysis. Corroborating previous studies, we propose that, during liver injury, two different cell types may be involved in repopulating the regenerating organ: (1) c-kit + (and likely Thy1 + ) HSCs which are mobilized from the BM and invade the liver through the circulation [39] and (2) endogenous OV6/CK19/Rab3b + oval cells which emanate from biliary ducts [12,32].…”

“…One population is endogenous to the hepatic tissue and, in our hands, is not prone to replication in vitro, while the second population would be derived from HSCs and able to transiently proliferate in culture. These data support the concept of the contribution of both resident liver stem cells as well as HSCs to hepatocellular regeneration [32]. However, caution should be taken on conclusions regarding the potential 'oval cell' origin of hepatic stem cell lines.…”

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…The TNAP-AID mouse model exhibits several characteristics of human HCC, in that the mice develop HCC spontaneously and the HCC tissue expresses a-fetoprotein and that it has the p53 gene mutations, some of which cause the same amino acid replacements as those seen in human tumours. Earlier HCC mouse models include mice with genetic modifications of Lkb1, Mdr2, Aox and Pten genes (Fan et al, 1998;Nakau et al, 2002;Horie et al, 2004;Katzenellenbogen et al, 2006), transgenic mice overexpressing c-myc, transforming growth factor-a, transforming growth factor-b1, HBx of hepatitis B virus and HCV core (Sandgren et al, 1989;Kim et al, 1991;Murakami et al, 1993;Koike et al, 1994Koike et al, , 2002Factor et al, 1997;Riehle et al, 2008) and chemical-or diet-induced HCC (Sell, 2001;Maeda et al, 2005;Ma et al, 2006;Sakurai et al, 2006). In contrast to these models, our TNAP-AID model is unique because it does not arbitrarily target specific oncogenes, tumour suppressors or stability genes.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…In the rodent model, DNA synthesis starts 12 to 16 hours after the standard partial hepatectomy (PHx) and peaks at 24‐48 hours. The original organ mass is almost restored 3‐7 days postresection, and by 3‐4 months in humans 95, 96. Liver regeneration therefore represents an example of precisely controlled initiation and synchronized cell proliferation in vivo , in which normally quiescent hepatocytes exit G0, reenter the cell cycle, and undergo one or two rounds of replication, with restoration of liver mass and function 94, 97, 98.…”