ENGINEERING ARTIFICIAL STEM CELL NICHES - Biologically-Responsive Hybrid Biomaterials - page 275

(in the epithelium), brain (in the subventricular zone of the hippocampus), bone
marrow (on the endosteal surface and near blood vessels) and muscle (beneath
the muscle fiber basal lamina). 5,7,8,14 Interestingly, the characteristic niche
structure and biochemical composition of stem cell niches appears to be
conserved from fruit flies to mammals.
The signals that control stem cells function in the niche in a spatially and
temporally well-controlled manner can be grouped into three main categories
(Fig. 1) : (i) direct physical contact with support cells via cell-cell interactions
providing short-range signals, (ii) contact with a surrounding protein- and sugar-
rich extracellular matrix (ECM), and (iii) exposure to soluble signals such as
growth factors, cytokines, chemokines or metabolic cues such as Calcium ions or
reactive oxygen species. Notably, blood vessels are often found near niches
(or are perhaps niches themselves), 15,16,17,18 presumably to transport long-range
signals and serve as a conduit for recruitment of circulating cells into the niche.
In addition, stem cells in niches can respond to inputs from the nervous system,
as demonstrated in the hematopoietic stem cell (HSC) niche. 19
1.2. Cell-cell interactions in the niche
Support cells provide transmembrane signals such as Cadherin proteins that
anchor the stem cells to their niches for example via so-called adherens junctions
(Fig. 1a and b) . The extracellular domain of Cadherins on support cells can
interact either with stem cell-derived Cadherins of the same kind ( i.e. homophilic
binding) or with different Cadherins ( i.e. heterophilic binding). 20 In studies on
fruit flies it has been shown that loss of Cadherin in stem cell niches leads to
stem cell loss as well, 21 underscoring the importance of adhesive cell-cell
interactions in the niche. In as much the Cadherin-mediated cell-cell interactions
are involved in regulating stem cell self-renewal is not well understood.
Cell-cell communication via transmembrane receptors in the stem cell niche
can also regulate functions beyond cell adhesion. For example, the family of
Notch receptors and their ligands Jagged and Delta have been associated with an
important role in stem cell regulation in diverse tissues. 22,23,24,25 Lack of Notch
signaling can for example result in a reduction of neural stem/progenitor cell
numbers, suggesting a role for this pathway in stem cell maintenance. 22