AN EFFICIENT EX VIVO EXPANSION OF ADULT MESENCHYMAL STEM CELLS IN SCAFFOLDS - Intelligent Scaffolds for Tissue Engineering and Regenerative Medicine - page 837

and others, 63 , 64 leading to migration, adhesion, proliferation, and
survival in various cell types 64 - 67 EGFRs are expressed on the sur-
faceofbonemarrowMSCs. 68 , 69 Tatama et al. haveshownthatstimu-
lationofimmortalizedhumanMSCsandprimaryporcineMSCswith
solubleEGFcanstronglyinducephosphorylationofEGFR,ERK,AKT,
and phospholipase C- γ . 41 EGF also partially promotes proliferation
in human primary bone marrow MSCs. 70 Consequently, EGF is able
to promote proliferation and migration of MSCs without affecting
theirmultipotency. 41 Inaddition,asignificantincreaseinclonogenic
growthofMSCs,asassessedbycolonyformingunit-fibroblast(CFU-
F) assay, occurs in response to EGF. 56 These results support that
EGF can significantly promote proliferation of MSCs and could be
used as a growth factor for ex vivo expansion. 41 On the other hand,
Kratchmarova et al . have shown that EGF can promote osteoblas-
tic differentiation of immortalized human MSCs. 71 The activa-
tion of intracellular signaling molecules was analyzed in response
to EGF as an osteogenic factor and PDGF as a negative con-
trol. Tyrosine phosphorylation of PI3K exclusively occurred in
response to PDGF, indicating the importance of PI3K in medi-
ating the differential effects of these two growth factors on the
osteogenic differentiation of MSCs. Furthermore, wortmannin, a
PI3K inhibitor, can drive PDGF-mediated signals toward osteogenic
differentiation. 71 Therefore, it will be interesting to see whether
the differential effects exerted on MSCs by growth factors can
be controlled by the use of chemical inhibitors of signaling
molecules.
The effects of surface modifications elicited by use of a scaf-
fold in combination with EGF have been demonstrated by Grif-
fith et al . Tethering of EGF to the scaffold surface allows EGF
to bind to the EGFR but inhibits internalization of the ligand 72
in a manner that resembles a matrix-embedded EGFR ligand. 41 , 73
In this study, surface-tethered EGF promoted both cell spreading
and survival more strongly than soluble EGF. MSC death induced
by Fas ligand, a proinflammatory cytokine, was also reduced
by EGF tethering. These results demonstrate that tethered EGF
offers not only a protective effect against inflammatory reactions
to scaffolds but also a stimulatory effect on the proliferation of
MSCs. 41