Biomedical Engineering Reference
In-Depth Information
problems in wound healing and die or have to be sacrificed in the first few weeks
after birth due to skin ulceration caused by depletion of a functional stem cell
pool (Wakel et al., 2001; Arnold and Watt, 2001). This might be due to a
reduction in adhesive interactions between stem cells and the local environment
allowing them to exit from their normal niche (Frye et al., 2003). Myc epidermal
knockout mice (KO) are viable and their keratinocytes continue to cycle, but
they display sever skin defects. In particular, keratinocyte cell size, growth
and endoreplication are reduced as well as stem cell amplification is compro-
mised (Zanet et al., 2005). Interestingly, this chapter suggests that stem cell
turnover is higher in KO Myc mice and that their compartment might be
reduced. Moreover, a consequence of forcing stem cells to divide is that the
epidermis would age prematurely, in fact the KO Myc skin mice appeared
atrophic and showed a slow regenerating capacity (Zanet et al., 2005). Ectopic
expression of c-Myc also renders keratinocytes resistant to growth inhibition by
TGFb1 (Alexandrow et al., 1995).
Tert is another factor which promotes stem cell mobilization in the absence
of changes in telomere length and beta-catenin stabilization which promotes the
transition from quiescent stem cells to proliferating cells in the bulge (Lowry
et al., 2005). When cells exit from the stem cell compartment, they undergo a
few further rounds of division, during which time they are known as transit-
amplifying cells. Thereafter, they undergo terminal differentiation along several
distinct lineages, forming the interfollicular epidermis, sebaceous gland and
hair follicle (Niemann and Watt, 2002).
Wnt signalling through b-catenin plays a pivotal role in controlling the various
stem cell populations in the mammalian body (Reya and Clevers, 2005). Wnt
ligands constitute a family of highly conserved secreted glycoproteins that acti-
vate a cascade of cellular signalling events known as Wnt/b-catenin signalling
pathways (Wodarz and Nusse, 1998; Logan and Nusse, 2004). In the skin, Wnt/
b-catenin signalling is important in cell fate determination, differentiation and
morphogenesis (Fuchs et al., 2001; Niemann and Watt, 2002; Millar, 2002).
Multiple Wnts and frizzled receptors are expressed in the skin in highly
dynamic patterns at different stages of development and provide good candi-
dates for mediating all the different effects attributed to the Wnt/beta-catenin
signalling cascade (Reddy et al., 2004; Millar, 2002). In vivo studies analysing
Wnt-responsive beta-galactosidase reporter in the skin revealed the strongest
activity in matrix cells at the base of the growing hair follicle (DasGupta and
Fuchs, 1999). In postnatal skin activated b-catenin was demonstrated to
induce new hair follicle structures from the interfollicular epidermis, the
sebaceous gland and the outer root sheath of existing hair follicles even
when the b-catenin signal is temporally restricted (van Mater et al., 1998; Lo
Celso et al., 2004). Remarkably, b-catenin-induced hair follicles compose a
bulge region with expression of stem cell markers and dermal papillae and can
undergo cycles of hair regeneration (Silva-Vargas et al., 2005). Thereby, Wnt/
b-catenin signalling levels determine the cell fate and lineage commitment in
the skin: strong activation of the pathway leads to stimulation of hair
