Microenvironment Design for Stem Cell Fate Determination - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 244

microenvironment, the proteoglycans heparin and heparan sulfate bind many
growth factors, chemokines and cell adhesion molecules, collectively known
as heparin-binding peptides, via high-affinity, specific electrostatic interactions
[ 161 , 162 ]. Such interactions are mediated by low- and high-sulfated sequences in
these glycosaminoglycan (GAG) chains [ 163 , 164 ]. In addition, binding affinity
values were found to depend on the degree of polysaccharide sulfation [ 165 , 166 ].
The proteoglycan interactions play a critical role in assembling protein-protein
complexes, such as growth factor-receptor or enzyme-inhibitor, on the cell sur-
face and in the ECM, which are directly involved in initiating cell signaling events
or inhibiting biochemical pathways [ 167 ]. For instance, the interaction of heparin/
heparan sulfate with fibroblast growth factor (FGF) has been shown to act as a
template that bridges the factor and its receptor, thereby effectively lowering the
concentration of FGF needed to initiate the signaling through its receptor and
extending the response duration [ 168 ]. Moreover, recent works have shown that
the presentation of VEGF in trans in association with heparan sulfate leads to
enhanced signal transduction by facilitating the formation of receptor-ligand
complexes and trapping of the active signaling complex [ 169 ].
Heparin-Based Biomaterials
Growing knowledge on the important roles of heparin/heparan sulfate has led to
numerous attempts to incorporate these materials in stem cell microenvironmental
design. For example, heparin functionalized PEG gels were shown to modulate
protein adsorption and promote hMSC adhesion and osteogenic differentiation
[ 170 , 172 ]. In these experiments, the heparin was modified with methacrylate
groups, copolymerized with dimethacrylated PEG to form a hydrogel, which
enabled a localized delivery vehicle for basic-FGF and served as a synthetic ECM
for the differentiation of hMSCs.
In another study, Willerth et al. [ 172 ] used a heparin-based delivery system for
mouse ESC differentiation inside fibrin scaffolds. The delivery system presented
three components: a bi-domain peptide, heparin and growth factor. The peptide
contained a Factor XIIIa substrate derived from a2-plasmin inhibitor, allowing it
to be covalently cross-linked into the fibrin scaffold, and a heparin-binding domain
derived from antithrombin III, which bound heparin non-covalently and retained it
inside the fibrin scaffold. The heparin could in turn bind growth factors and retain
them inside the scaffold. This delivery system was used to deliver different mol-
ecules, such as platelet-derived growth factor (PDGF), at various doses. The
controlled delivery of these molecules simultaneously increased the fraction of
neural progenitors, neurons, and oligodendrocytes while decreasing the fraction of
astrocytes obtained, compared to control cultures seeded inside unmodified fibrin
scaffolds with no growth factors present in the medium [ 172 ].
Recently, Webber et al. [ 173 ] used a heparin-presenting nanofiber network to
bind and deliver paracrine factors derived from hypoxic conditioned stem cell
media to mimic the stem cell paracrine effect, for cardiovascular disease treatment.