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two stages: refractory to the induction of anagen and a competent stage wherein
secondary hair germ cells become highly sensitive to anagen-inducing factors
(Plikus et al. 2008 ). The BMP2 and 4 signals derived from dermal papilla cells
inhibit activation of the Wnt/β-catenin pathway in the epithelial cells of the second-
ary hair germ (Plikus et al. 2008 ). Conclusive studies have demonstrated that
extra- follicular BMP signals, which are provided by undifferentiated progenitors
of adipocytes in the subcutaneous adipose, also override the entry of competent
telogen into anagen and are negatively regulated by epithelial adipogenetic factors
(Plikus et al. 2008 ; Festa et al. 2011 ; Rivera-Gonzalez et al. 2014 ; Hsu et al. 2014 ).
Additionally, several observations have suggested that the skin peripheral nerve
connected to the hair follicle controls enlargement of the hair follicle during anagen
(Peters et al. 2006 ; Hsu et al. 2014 ).
6.4 Epithelial and Mesenchymal Stem Cells in the Adult
Hair Follicle
To achieve iteration of the hair cycle, maintenance of the various adult stem cells
and their niches in the mature hair follicle is considered to be essential throughout
the lifetime of the organism (Cotsarelis et al. 1990 ; Greco et al. 2009 ). The most
essential hair follicle stem cells (i.e., the minimal cell elements for the reconstruc-
tion of the entire hair follicle) are epithelial and mesenchymal stem cells
(Botchkarevn and Kishimoto 2003 ). When the lower half of the hair follicle is surgi-
cally ablated, the remaining upper portion cannot regenerate a hair bulb (Jahoda
et al. 1984 ; Horne et al. 1986 ). Surgical destruction of the area between a sebaceous
gland and the arrector pili muscle connecting the portion of the human hair follicle,
which is referred to as the bulge region, causes irreparable damage to the hair fol-
licle and is applied clinically for hair removal operations (Unger et al. 2010 ).
Moreover, reconstruction experiments of the bulge epithelium and dermal papilla or
dermal sheath cup demonstrated that a structurally and functionally complete hair
bulb can be regenerated by reproducing the epithelial-mesenchymal interactions,
similarly to anagen of the natural hair follicle (Jahoda et al. 1984 ; Horne et al.
1986 ). These observations directly indicate that the hair follicle epithelial stem cells
and mesenchymal stem cells are localized in stem cell niches in the bulge region and
lower variable region, respectively (Lavker et al. 2003 ; Schneider et al. 2009 ).
The major biological characteristics of stem cells in vivo are quiescence, a high
proliferative capacity, and multipotency to produce multiple lineage cells (Claudinot
et al. 2005a, b). Slow cycling epithelial cells of the adult hair follicle are detected as
label-retaining cells in the bulge region, and lineage analysis has shown that all fol-
licular epithelial cells originate from bulge ORS epithelial cells (Oshima et al. 2001 ;
Claudinot et al. 2005a, b; Ohyama et al. 2006 ; Waters et al. 2007 ). Several research-
ers have reported that certain markers, such as cytokeratin 15 (CK15), CD34, and
K.-e. Toyoshima and T. Tsuji