Artificial Scaffolds and Mesenchymal Stem Cells for Hard Tissues - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 179

also a substrate in signal transduction pathways, and a major factor in the SC niche
for self-renewal [ 184 ] and survival under ischemic stress by maintaining the
multipotency of MSCs [ 185 ]. Cyclic adenosine monophosphate (cAMP) can
induce differentiation in epidermal and neuronal cells similarly to RA, and com-
bined with cytokines, cAMP seem to improve viability and function of hemato-
poietic cells [ 186 ]. ATP and UTP, as well as their breakdown products, signal
through a family of so-called P receptors, which is composed of four P1 and 15 P2
receptors. Recently it has been shown that the P2 receptors in particular play a
major role in MSC proliferation and differentiation into the adipogenic and oste-
ogenic lineages [ 187 ]. Exploring this receptor family can also be expected to shed
more light on the known effect of calcium ions within the SC microenvironment,
since the subfamily of P2X receptors are ligand-gated ion channels as well [ 188 ].
To round off the story, it should be mentioned that they also are a source of
cytokine secretion (see Fig. 5 ).
Cell-cell interactions seem to be fundamental for differentiation control.
An example is Notch signaling, which has been described to influence asymmetric
cell division [ 189 ]. The interactions between SCs and neighboring cells are best
understood for the bone marrow-located niche of the HSCs. An overview of
the cells contributing to the maintenance of a functional HSC niche, which
are composed of sinusoidal endothelial cells, macrophages, perivascular MSCs,
sympathetic nerve fibers, and of course the cells of the osteoblastic lineage
regulating the behavioral control of HSCs, is given in the review of Ehninger and
Trumpp [ 190 ]. The network of cytokine interactions and enzymes yielding
the particular response of these SCs is summarized in the review of Visigalli
and Biffi [ 191 ]. Another fairly well characterized niche is the hair follicle.
Wnt/b-catenin is required for follicle SC maintenance and b-catenin activation is
crucial for inducing quiescent follicle SCs to proliferate and terminally differen-
tiate along the hair cell lineage [ 192 ].
For other SC niches, various components have been described [ 179 ], but the
overall picture is as yet unclear. It is clear that several cytokines such as
interleukin 11 (IL-11) in the HSCs' fate are another group of key players in SCs'
fate. Another example is IL-6, which triggers the maintenance of human limbal
epithelial cells in a progenitor-like state [ 193 ]. However, knowing the components
is not enough. The local concentration might cause a threshold-based reaction and
the soluble factors interact with the solid-state signals. Much work must be
devoted in the future to elucidating in more detail the concerted action of the
multiple temporal and spatial factors, which often cause the SCs to react in a
synergistic way with a specific cell fate response that ultimately leads SCs to
organize into tissues which organize into organs. Microscale engineering strategies
for systematically examining and reconstructing individual niche components
might be a way to shed more light on the complex composition of the SC
microenvironment [ 194 ]. There is no doubt that synthetic SC niche engineering
may form a new foundation for regenerative therapies.