Biomedical Engineering Reference
In-Depth Information
an exocrine system in the liver, connects the apical surface of hepatocytes to the
intestine through bile canaliculi, which drain into the canals of Hering and finally
into bile ducts [
3
]. Two afferent vessels, the hepatic artery and the portal vein
provide the blood supply for the liver. Their terminal branches enter the liver
sinusoids, which are characterized by fenestrated and discontinuous endothelium
[
1
]. No basement membrane lines the sinusoid, which allows higher permeability
and direct transfer of particles less than 100 nm from the vessels to the basolateral
surface of the hepatocytes.
The adult liver is a quiescent organ and as few as one out of 3,000 hepatocytes
divides at a given time point to maintain the physiological liver mass. In acute
liver damage or through surgical loss of liver mass, however, cell proliferation can
be extensively accelerated until the tissue mass has been restored [
4
]. In only 7
days up to 75 % surgically removed liver mass can be regenerated in rodents [
5
].
Although the term ''liver regeneration'' is commonly used, restoration of the liver
mass after partial hepatectomy is actually a form of compensatory growth of the
remaining liver (hyperplasia).
In the regenerative phase after acute liver injury or tissue loss the liver immedi-
ately induces more than 100 genes, which are not expressed in normal liver [
6
,
7
]. The
early changes in gene expression reflect both the entry of hepatocytes into the cell
cycle as well as the orchestration of specific adjustments that hepatocytes have to
make, so that they can deliver all essential hepatic functions while going through cell
proliferation. The extensive ''reprogramming'' of hepatic gene expression requires
activation of multiple signaling pathways involving matrix remodeling proteins,
growth factors, cytokines, paracrine signals, and neuroendocrine factors.
Small non-coding RNAs, mainly microRNAs (miRNAs), provide an additional
level of regulation in liver regeneration. Global loss of miRNAs leads to the
impairment of hepatocyte proliferation at the G1-S stage of cell cycle. In partic-
ular, miR-21, one of the upregulated miRNAs in HCCs, has been shown to
increase the proliferation of hepatoma cells by targeting Pten and Btg2. As of now,
data are limited and mainly restricted to the initiation phase of liver regeneration.
Importantly, in vivo functions of individual miRNAs during liver regeneration
have not yet been identified.
The newborn liver contains mostly diploid hepatocytes, but polyploidization
and binuclearity occur rapidly after birth. In perivenous areas hepatocytes are more
often polyploid and serve different liver functions when compared to cells of the
periportal region (''metabolic zonation'') [
8
,
9
]. The gradient of less complex cells
with higher proliferation potential (in vitro) in periportal areas and more mature
hepatocytes in perivenous areas has been interpreted as evidence for the existence
of a physiological niche for cell renewal [
10
] in the periportal region. Recent
experimental studies of hepatocytes with acquired mitochondrial mutations in the
cytochrome c oxidase gene have also provided arguments for the periportal region
as the ''regenerative niche'' in normal liver [
11
]. The ''streaming liver hypothesis''
postulating that the liver lobule is organized similar to the intestinal crypt and
contains a stem/progenitor cell pool arising form the periportal area, however, has
been disputed [
12
].
