Biomedical Engineering Reference
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Fig. 10.1 Relative contribution of primary mouse hepatocytes and liver progenitor cells to liver
regeneration (Adapted from [
21
])
Regenerative responses and cell types involved differ depending on the severity
and chronicity of liver injury. Although it is not debatable that mature hepatocytes
and cholangiocytes represent the first and most important resource for tissue repair
[
13
,
14
], a liver stem/progenitor cell compartment is likely to be involved in the
repair of injured livers.
The first evidence for the existence and activation of a resident hepatic stem/
progenitor cells compartment was provided by various murine animal models of
''oval cell'' proliferation [
15
-
19
]. The general principle underlying ''oval cell''
activation is based on the combination of a liver injury and the inability of
hepatocytes to proliferate in response to the damage. The extent, to which liver
stem/progenitor cells contribute to parenchymal liver regeneration in various
forms of liver injury was lately controversely discussed. Furuyama et al. reported
that liver progenitor cells residing in bile ducts are the predominant source of new
hepatocytes in mouse liver homeostasis as well as in liver injury [
20
]. The data
were challenged by a new hepatocyte fate tracing model, which demonstrated only
a minor role of stem/progenitor cells for the generation of hepatocytes and biliary
epithelial cells in normal and injured liver [
21
] (Fig.
10.1
).
In parallel to what we know from rodent models, also in human liver diseases
the inhibition of mature hepatocyte replication favors the proliferation of cell
populations with stem/progenitor phenotypes. Activation of these cells has been
associated with a variety of liver diseases, and, the numbers have been related to
severity of the disease [
22
,
23
]. It has recently been shown that hepatocytes
become senescent, owing at least partially to telomere shortening, in the cirrhotic
stage of a wide variety of chronic human liver diseases [
24
,
25
]. Replicative
exhaustion and senescence of the mature hepatocytes as a result of ongoing pro-
liferation during 20-30 years of chronic liver disease has been linked to the
emergence of these stem/progenitor cells and finally with the evolution of hepa-
tocarcinoma and cholangiocarcinoma [
26
,
27
]. However, it is unclear whether
these cells are simply a marker of carcinogenic disease states or whether the stem/
progenitor cells are at particular risk for transformation.
