Biomedical Engineering Reference
In-Depth Information
differentiation such as Gas1 and tenascin C. Recent studies also demonstrated
the crucial roles of Rac1 and Lhx2 for the maintenance of hair follicle stem cells
(Benitah et al., 2005; Rhee et al., 2006). In particular, mouse bulge markers
include CD34 keratin 15 (K15) and the b4 and b1 integrin subunits (Fuchs et al.,
2004; Morris et al., 2004; Tumbar et al., 2004; Cotsarelis, 2006). Recently, the
genes upregulated in the bulge of mouse and human hair follicles have been
compared (Cotsarelis, 2006; Ohyama et al., 2006). K15 is a bulge marker in both
species, but in human follicles CD34 is expressed below the bulge (Lyle et al.,
1998). Laser capture microdissection and microarray analysis revealed a panel
of cell surface markers for human bulge cells. CD200 and CD59 are upregulated
in the bulge compared to other defined hair follicle regions, while CD24, CD34,
CD71 and CD146 were downregulated (Ohyama, 2007). In particular, CD200
was preferentially distributed in the bulge area and represented the best positive
surface marker for the human bulge cells (Ohyama, 2007). It is an interesting
marker since it plays a role in the communication with the immune system
(Cotsarelis, 2006; Ohyama et al., 2006). On the other hand, the expression of
Dkk3 and Wif1 (Wnt-inhibitor factor 1) in the mouse and human bulge under-
scores the importance of genes that maintain stem cells in a nonproliferative
state. Although integrin-mediated adhesion to the extracellular matrix nega-
tively regulates terminal differentiation of cultured keratinocytes, epidermal
deletion of integrins in vivo does not lead to a stem cell depletion phenotype too
(Lopez-Rovira et al., 2005). In contrast, deletion of Rho family GTPase Rac1,
which regulates cell adhesion and growth factor responsiveness, results in stem
cell depletion and in the failure to maintain the interfollicular epidermis, hair
follicles and sebaceous glands (Benitah et al., 2005). Rac1 plays an important
role in the epidermis because Rho signalling suppresses differentiation of
cultured keratinocytes as does the Rho effector citron kinase (CRIK). Rho
and CRIK might act by affecting integrin and Notch signalling (Grossi et al.,
2005). One way in which Rac1 maintains the stem cell compartment is by
negative regulation of Myc. This occurs through PAK2 phosphorylation of
Myc, which decreases Myc binding to Max and DNA (Benitah et al., 2005). In
the skin epidermis, c-Myc is expressed in both the proliferative basal layer,
which comprises stem-progenitor cells and transient-amplifying cells, and the
bulge region that contains multipotent epidermal stem cells (Bull et al., 2002).
Activation of Myc causes cells to exit from the epidermis stem cell compartment
and stimulates differentiation into interfollicular epidermis and sebaceous
glands. Another way, Myc acts by Miz1-dependent repression of cell adhesion
genes, including the b6andb1 integrin subunits (Gebhardt et al., 2006). More
recently, Myc was demonstrated to trigger transit-amplifying divisions by
inducing expression of growth promotion genes such as Misu (Frye and Watt
2006). Although overexpression of Myc triggers terminal differentiation, ablat-
ing Myc from the epidermis results in insufficient expansion of the stem cell
compartments (Zanet et al., 2005). Thereby, stem cells seem to require low level
of Myc to proliferate and Myc-induced differentiation preventing uncontrolled
proliferation. Transgenic mice that express c-Myc in the basal cells suffer from
