Biomedical Engineering Reference
In-Depth Information
biological activity.
12
,
13
It is now clear that many growth factors
and cytokines can not only bind with high a
nity to their sig-
naling receptors but also bind with lower a
nity to matrix mole-
cules, such as proteoglycans, on cell surfaces or within the ECM. For
example, heparan sulfate proteoglycans bind to hepatocyte growth
factor (HGF)
14
andinturnstabilizeHGFoligomers,whichthenfacil-
itate the dimerization and activation of the HGF-signaling receptor
c-Met in hepatocytes.
15
The involvement of the ECM was also found
intheactionofothergrowthfactors,suchasbasicfibroblastgrowth
factor
16
and vascular endothelial growth factor.
17
In some cases,
onlycertainisoformscanbindtospecificECMmolecules,
18
-
20
which
therefore can lead to localization of certain growth factors in spe-
cialregion.BindingofgrowthfactorstotheECMcanalsoformlong-
range gradients or limit growth factor diffusion to one direction.
12
Knowledgeofgrowthfactor-ECMinteractionswillcertainlyprovide
guidance in scaffold design to tether growth factors in an appropri-
ate spatial manner.
ECM molecules and growth factors are produced by different
types of cells in the epithelial tissues. In the liver, hepatocytes
produce heparan sulfate proteoglycans, endothelial cells produce
laminin, and hepatic stellate cells produce type IV collagen and
laminin, whereas activated hepatic stellate cells produce types I
and III collagen.
21
HGF is a paracrine factor, being secreted by non-
parenchymalcellsandactiveinhepatocytes.Therefore,co-culturing
is an effective means to temporally and spatially provide biological
cues for epithelial cells.
The ECM is dynamic during development
22
and is not uniform
across the adult epithelial tissues. Laminin, types III and IV colla-
gen, and hyaluronans are predominant in fetal and neonatal livers,
while fibronectin is dominant in the adult livers.
11
There is a gra-
dient in the adult liver matrix composition from the portal triad to
the central vein, with more type IV collagen, laminin, and heparan
sulfate proteoglycans in the periportal area and more type I colla-
gen,fibronectin,andheparinproteoglycansinthepericentralarea.
23
This gradient provides a stem cell niche, influencing self-renewal
and differentiation of hepatic progenitors: hepatic stem cells and
hepatoblasts.
24
,
25
When progenitors are used in epithelial tissue
engineering, different strategies must be used to present the stem
cell microenvironment.
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