Biomedical Engineering Reference
In-Depth Information
1.4 Microenvironmental
Influences on Bone Formation
by Stem Cells
differentiation, the number of passages in
culture, the health status of the stem-cell donor,
and the tissue from which the cells have been
obtained are all variables that infl uence the
fi nal differentiation potential of the stem cells.
For example, culturing ADSCs on hydroxyapa-
tite scaffolds in the presence of BMP-
Several factors are critical to the successful for-
mation of bone by stem cells. The osteopoten-
tial of a stem cell is signifi cantly infl uenced by
environmental signals that include soluble
growth and differentiation factors, as well as
cell-cell and cell-ECM interactions. When stem
cells are delivered either ectopically or into a
critical size defect model in a soluble vehicle
solution such as physiologically balanced
saline, relatively few stem cells are actually
found to multiply and differentiate into osteo-
blasts [
prior to
implantation appears to aid in bone formation
[
2
], whereas in vitro stimulation of these
same cells on the same scaffolds with other
osteoinductive reagents, such as dexametha-
sone or
23
,
92
-dihydroxyvitamin D
3
, may or may
not aid in bone formation [
1
,
25
38
,
40
]. Hattori and
colleagues [
] demonstrated that human
ADSCs are superior to undifferentiated cells
for the formation of ectopic bone when seeded
onto atelocollagen matrices cultured in the
presence of dexamethasone, ascorbate, and
β
52
]. One reason for this may be a lack
of adequate environmental signals to direct the
stem cells toward osteogenesis. However, when
the stem cells are allowed to adhere to a bone or
bonelike matrix, either alone or in the presence
of endogenous signals such as bone morphoge-
netic protein
60
,
92
-glycerol phosphate. Hicok and colleagues,
however, found that when dexamethasone and
1
-dihydroxyvitamin D
3
were used to pre-
differentiate ADSCs, there was no benefi t to
ectopic bone formation [
,
25
].
The age of the donor from which the stem
cells are derived may be important in deter-
mining the extent of predifferentiation required
for effective bone formation. Mendes demon-
strated that MSCs derived from either young or
old donors, when implanted subcutaneously
into nude mice, formed ectopic bone without
dexamethasone pretreatment. However, dexa-
methasone signifi cantly increased bone forma-
tion in implants that contained cells from
individuals older than
40
2
(BMP-
2
), retinoic acid, dexa-
methasone, or
-dihydroxyvitamin D
3
, bone
formation is increased [
1
,
25
].
Various natural and artifi cial scaffold mate-
rials have been utilized to serve as a delivery
vehicle for stem cells and to provide the cells
with appropriate cell-matrix interactions. Gen-
erally, these scaffolds are composed of either
autologous or allogenically derived bone,
demineralized bone matrix, coral, collagen,
calcium salts, or composites of these. Typically,
the more similar a scaffold is to natural bone,
the better it supports new bone growth. Thus,
scaffolds containing tricalcium or bicalcium
phosphate salts and hydroxyapatite appear to
be most effective in supporting stem-cell osteo-
genesis. Studies performed in a canine segmen-
tal defect model illustrate how adult stem cells
loaded onto an appropriate scaffold, a hydroxy-
apatite/
23
,
38
,
92
].
Other age- dependent factors, such as advanced
glycation end products from elderly or diabetic
recipients, inhibit stem cells from proliferating
and differentiating into osteoblasts [
50
years of age [
78
].
The concentration of osteoinductive factors
and the length of exposure to them affect stem-
cell effi cacy both in vitro and in vivo. ADSCs
that were genetically modifi ed to express either
constitutive BMP-
62
-tricalcium phosphate ceramic, can
repair large gaps within long bones [
β
demonstrated
increased levels of osteoid formation in com-
parison with stem cells cultured with these mol-
ecules [
2
or BMP-
7
]. Other
groups have utilized collagen-based scaffolds,
poly(lactic acid) (PLA) polymers, and hydro-
gels, with variable success; however, these
appear to be more suitable for cartilage forma-
tion [
18
]. Epigenetic modifi cation of the
stem cells may also be important, since com-
pounds such as valproic acid, which has histone
deacetylase inhibitory activity, have been shown
to enhance osteogenesis of both adipose-derived
and bone marrow-derived stem cells [
92
,
123
].
Determining the optimal combination of
soluble factor and matrix signals that gives rise
to stem-cell osteogenesis is complicated. Stem-
cell response to these signals may be model-
and species-dependent. The length of time for
26
,
38
,
40
,
61
,
113
].
Species-specifi c differences in the respon-
siveness of stem cells to their environment
further complicate our understanding of which
22
