Biomedical Engineering Reference
In-Depth Information
Introducing Matrix Metalloproteinase-Sensitive Peptides
The overall complexity of cell regulation is further increased by the dynamic
nature of regulatory signal presentation, which changes in space and time. Also,
the interactions between the cells and their environment occur in both directions.
Cells both respond to and actively modify the properties of their environment by
synthesizing or degrading the ECM, secreting cytokines, and communicating with
other cells and matrix via molecular and physical signals.
Thus, bio-inspired scaffolds have been developed to incorporate enzyme-
sensitive peptide sequences [ 100 , 138 - 141 ]. Such enzymatically cleavable mate-
rials exploit the upregulation and downregulation of cell-secreted enzymes, such
as matrix-metalloproteases (MMPs), to dictate material degradation on a local and
cellular timescale. For example, Kraehenbuehl et al. [ 99 ] fabricated cross-linked
PEG hydrogels incorporating adhesive (RGDSP) and enzymatically degradable
MMP-sensitive peptide as cross-linkers of the matrix. The matrices promoted ESC
differentiation into the cardiac lineage, probably via ligation of cell integrins
relevant in early cardiac development (a5b1, avb3) to the matrix-immobilized
RGDSP peptide. Further cardiac maturation was promoted by the MMP-sensitivity
of the matrix, allowing cell-triggered matrix remodeling [ 99 ].
Moreover, in an attempt to mimic the dynamic nature of the stem cell
microenvironment, where signaling events vary in time, the MMP-sensitive
peptides can be also exploited as a linker for other functional peptides in order to
control their temporal presentation in culture. For example, natively, hMSCs
differentiating into chondrocytes initially produce the adhesion protein fibro-
nectin, which is subsequently downregulated between days 7 and 10, while the
excreted ECM is remodeled through enzyme production. Therefore, Salinas et al.
[ 104 ] designed an adhesive sequence, RGD, with an MMP-13 specific cleavable
linker to release RGD, mimicking the native differentiation timeline. The
researchers showed that active MMP-13 production of encapsulated hMSCs
increased from days 9-14 specifically in the chondrogenic differentiating cultures
[ 104 ]. Their results pointed out the beneficial effect of the MMP-regulated
presentation
of
RGD
in
the
hydrogel
on
encapsulated
hMSC
chondrogenic
differentiation.
Introducing Growth Factors-Derived Peptides
Instead of supplementing the signals as soluble factors, short peptides derived
from growth factors and covalently bound to matrix were shown to be valuable
in affecting stem cell fate. The potential advantages of such a strategy are
better control over ligand presentation and the relatively prolonged stability of
the short peptides compared to the full growth factor. For example, Saito et al.
[ 142 ] could identify a BMP2-derived peptide (KIPKASSVPTELSAISTLYL),
shown to enhance the osteogenic differentiation of a murine multipotent
mesenchymal cell line, as indicated by alkaline phosphatase activity and gene
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