Biomedical Engineering Reference
In-Depth Information
vector (AdMMP8) as a therapeutic agent in cirrhosis using CCl
4
and bile duct-
ligated cirrhotic rats models. Liver fibrosis in bile duct-ligated cirrhotic animals
was decreased by 45 % along with reduced hydroxyproline levels in AdMMP8
treated animals. Treatment in both models correlated with improvements in
ascites, functional hepatic tests, and gastric varices indicating diminished portal
hypertension in animals injected with AdMMP8 [
87
].
Alternative treatment concepts aim to protect existing hepatocytes and/or to
increase the hepatocyte mass. Hepatocyte growth factor (HGF), originally iden-
tified and cloned as a potent mitogen for hepatocytes [
88
-
91
] has mitogenic and
morphogenic activities for a wide variety of cells [
92
,
93
] and also plays an
essential role in the development and regeneration of the liver [
94
]. The protein
has also been shown to have antiapoptotic activity in hepatocytes [
95
]. Trans-
duction of the HGF gene has suppressed the increase of transforming growth
factor-b1 (TGF-b1), which plays an essential part in the progression of liver
cirrhosis and inhibited fibrogenesis and hepatocyte apoptosis leading to complete
resolution of fibrosis in the cirrhotic liver in a rat model [
96
].
10.5.2.1 Stem Cell Therapy of Chronic and Acute of Chronic Liver Disease
Although the concept of stem cell therapy for various diseases is principally
accepted, the practical approach in humans remains difficult. Bone marrow derived
mononucleated cells, hematopoietic stem and progenitor cells, mesenchymal stem
(stromal) cells and sinusoidal endothelial cells are currently being investigated.
There are several proposed mechanisms by which stem and progenitor cells might
support regeneration in targeted organs including the liver: intercellular signaling
through cell-cell contacts, paracrine signaling (growth factors, cytokines, and
hormones) or cell fate change in the target organ.
The concept of stem/progenitor cell infusions exerting a paracrine regenerative
effect on the liver is gaining support and is backed up by both rodent and human
studies, although the latter are small and uncontrolled. Endothelial precursor cells
(EPC) have been shown in rodent models to promote angiogenesis and the deg-
radation of liver scar tissue thereby contributing to liver regeneration [
97
-
99
]. By
participation in neovascularization and by the expression of multiple growth
factors, transplanted EPCs significantly accelerate liver regeneration. This is
achieved by enhancing proliferative activity of hepatocytes leading to improved
survival after chemically induced liver injury [
97
].
Sakaida et al. have demonstrated that transplanted bone marrow cells degrade
extracellular matrix in carbon tetrachloride (CCl
4
)-induced liver fibrosis, with a
significantly improved survival rate in this animal model. Their findings suggest
that transplanted bone marrow cells can degrade collagen fibers and reduce liver
fibrosis by strong expression of MMPs, especially MMP-9 [
100
].
Other groups have raised concerns about the role of certain subtypes of bone
marrow stem cells in chronic liver injury [
101
]. It has been shown that bone
marrow-derived
myofibroblasts
significantly
contributed
to
fibrogenesis
in
a
