Biomedical Engineering Reference
In-Depth Information
The mechanisms that regulate the above fates, in particular the delicate
balance between cell divisions that lead to self-renewal and/or differentiation, are
still under intense investigation.
45,46,47,48
The decision of a stem cell to undergo an
asymmetric division may be controlled by cell-intrinsic and/or cell-extrinsic
mechanisms. In the first scenario, intracellular segregation of certain intracellular
protein components may drive asymmetry.
46
On the other hand, the asymmetric
positioning of daughter cells relative to external niche components may also
induce asymmetric divisions.
48
In this case, both daughter cells may initially be
equivalent, but their different microenvironments may impose two disparate
identities. During development or when experiencing stress, adult stem cells in
the niche must increase in numbers which can only occur via symmetric self-
renewal divisions giving rise to two daughter stem cells
(Fig. 2c)
. A symmetric
division could, for example, be controlled by cell-extrinsic mechanisms, if both
daughter cells encounter the same niche environment after division and remain
in the niche as stem cells. Notably, the same stem cell populations appear to
switch from symmetric divisions during embryonic development or regeneration
in the adult to asymmetric cell divisions during late fetal development and
homeostasis.
49,50
The interplay between stem cells and their niches therefore creates a dynamic
and reciprocal system that balances stem cell numbers in response to the
physiological demands of the tissue
(Fig. 3)
. Consequently, the size of the stem
cell pool has been shown to correlate with the size of the niche.
7
For example,
when a change in numbers of support osteoblasts in the bone marrow niche was
induced
51,52
, accompanying changes in the HSC pool size were observed.
Specific signals keep the number of stem cells in the niche constant during
homeostasis
(Fig. 3a)
and allow the stem cell pool to expand under physiological
stress and in pathological situations such as cancer
(Fig. 3b)
where the tightly
orchestrated regulation of cell numbers is misregulated.
Finally, it is conceivable that multiple types of niches exist for each stem cell
type. Although still debated, HSCs are believed to transit from an endosteal
niche, wherein they adhere to osteoblasts and remain quiescent, to a vascular
niche, wherein they become activated due to interaction with endothelial cells on
blood vessel walls. Thus, the nature of the two niches may dictate the state of
activity of the stem cell
18,53,54,55
. As well, it is likely that niches can be formed or
destroyed in response to physiological needs. In the absence of functional niches,
symmetric differentiation divisions
(Fig. 2d)
could lead to a rapid depletion of
the stem cell pool
(Fig. 3c)
, therefore impairing further production and leading
to loss of tissue function. This may explain why to date many adult stem
cell populations cannot be maintained in culture. Indeed, when plated on
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