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New Activators and Inhibitors in the Hair Cycle Clock: Targeting Stem Cells’ State of Competence

      The timing mechanism of the hair cycle remains poorly understood. However, it has become increasingly clear that the telogen-to-anagen transition is controlled jointly by at least the bone morphogenic protein (BMP), WNT, fibroblast growth factor (FGF), and transforming growth factor (TGF)-β signaling pathways. New research shows that Fgf18 signaling in hair follicle stem cells synergizes BMP-mediated refractivity, whereas Tgf-β2 signaling counterbalances it. Loss of Fgf18 signaling markedly accelerates anagen initiation, whereas loss of Tgf-β2 signaling significantly delays it, supporting key roles for these pathways in hair cycle timekeeping.

      Hair cycle clock

      One of the most intriguing questions in hair biology is what controls the hair cycle, a repetitive process of hair follicle regeneration. The hair cycle is typically divided into resting, growing, and involution phases, referred to as telogen, anagen, and catagen, respectively. The duration of anagen determines the length of the hair shaft produced by the follicle, whereas the duration of telogen determines how soon a new hair shaft is made. Telogen-to-anagen and anagen-to-catagen transition events must be highly regulated, as they contribute to the achievement of a hair coat of optimal length and density, which is essential for the survival and adaptation of many mammals. The mechanism regulating the anagen-to-catagen transition targets proliferating matrix cells and induces them to undergo coordinated apoptosis, likely via signaling switches from within the matrix and/or in adjacent dermal papillae. The telogen-to-anagen transition mechanism targets progenitor populations of the bulge and hair germ, causing them to exit quiescence. This latter process has received much attention in recent years, shedding light on the general aspects of stem cell niche biology in other tissues and organs.

      “Social networking” between hair follicles

      Until recently, the hair follicle was considered a relatively closed system and was treated as such in the context of many experimental models. This concept worked fairly well for many purposes, partly because laboratory mice do not have obvious seasonal hair growth and partly because many experiments were designed around the first and second postnatal hair cycles, when hair growth stages can be reliably associated with the age of the animal. Studying the hair cycle in adult mice was thought to be difficult because telogen-to-anagen transition events could not be predicted, and, when they occurred, would result in patches of hair growth that appeared to be random.
      Recent inquiries into the adult hair cycle have revealed several interesting facts. The quiescence of hair follicle progenitor cells is maintained not only by the immediate niche microenvironment but also by the larger dermal macroenvironment. The microenvironment consists of the dermal papilla, the dermal sheath, and keratin 6–positive bulge cells, whereas the macroenvironment includes dermal fibroblasts, cutaneous adipocytes (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ), preadipocytes (
      • Festa E.
      • Fretz J.
      • Berry R.
      • et al.
      Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.
      ), and probably other extrafollicular components such as intradermal blood vessels, the nerve plexus, and immune cells (Figure 1). Neighboring hair follicles also communicate with one another during the telogen-to-anagen transition, exchanging growth-inducing signals (
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ). Curiously, signaling pathways previously implicated in autonomous anagen initiation—bone morphogenic protein (BMP) (
      • Botchkarev V.A.
      • Botchkareva N.V.
      • Nakamura M.
      • et al.
      Noggin is required for induction of the hair follicle growth phase in postnatal skin.
      ) and WNT (
      • Lowry W.E.
      • Blanpain C.
      • Nowak J.A.
      • et al.
      Defining the impact of beta-catenin/Tcf transactivation on epithelial stem cells.
      ;
      • Enshell-Seijffers D.
      • Lindon C.
      • Kashiwagi M.
      • et al.
      β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair.
      )—are reused to mediate follicle-to-follicle and macroenvironment-to-follicle communications.
      Figure thumbnail gr1
      Figure 1Signaling changes in the hair follicle during telogen and upon anagen initiation. Hair follicles are exposed to a different signaling environment during competent telogen than during refractory telogen. (a) In the refractory phase, a high level of inhibitory bone morphogenic protein (BMP) signaling is attributable to the multiple Bmp ligands produced by the hair follicles themselves (
      • Botchkarev V.A.
      • Botchkareva N.V.
      • Nakamura M.
      • et al.
      Noggin is required for induction of the hair follicle growth phase in postnatal skin.
      ;
      • Blanpain C.
      • Lowry W.E.
      • Geoghegan A.
      • et al.
      Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.
      ,
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ) and by the surrounding dermal macroenvironment (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ). Activating WNT signaling is low, partly because of the WNT antagonists present in the dermal macroenvironment (
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ). Inhibitory fibroblast growth factor (Fgf)18 signaling (mediated by Fgfr3/4 receptors) is high (
      • Blanpain C.
      • Lowry W.E.
      • Geoghegan A.
      • et al.
      Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.
      ;
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ;
      • Hsu Y.C.
      • Pasolli H.A.
      • Fuchs E.
      Dynamics between stem cells, niche, and progeny in the hair follicle.
      ;
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      ), whereas activating Fgf7 signaling (mediated by the Fgfr2-IIIb receptor) is very low (
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ). (b) Upon transition into the competent telogen phase, overall BMP signaling decreases and WNT signaling increases, partly because of the signaling threshold switch operating in the dermal macroenvironment (
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ) and partly as a result of increased production of Wnts, BMP antagonists, and transforming growth factor (Tgf)-β2 by hair follicles themselves (
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ;
      • Oshimori N.
      • Fuchs E.
      Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
      ). During competent telogen, dermal papillae begin to produce more of the activating Fgf7 and less of the inhibitory Fgf18 (
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ). It is uncertain whether Fgf18 production by bulge cells changes from refractory to competent telogen. (c) Upon telogen-to-anagen transition, hair follicles experience transient activation of canonical WNT signaling, first in dermal papillae (
      • Enshell-Seijffers D.
      • Lindon C.
      • Kashiwagi M.
      • et al.
      β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair.
      ;
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ) and then in epithelial progenitor cells (
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ). The WNT activation event is partly fueled by Wnt ligands secreted by neighboring anagen hair follicles. This so-called signaling coupling between neighboring telogen and anagen hair follicles likely occurs across multiple signaling pathways; the exact details of this process remain unknown. It is likely that the dermal macroenvironment provides activating signals during anagen initiation as well. Recently, dermal preadipocyte-derived platelet-derived growth factor (PDGF) emerged as one such activator (
      • Festa E.
      • Fretz J.
      • Berry R.
      • et al.
      Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.
      ).
      As a population, pelage hair follicles strive to regenerate as seldom as possible. Telogen follicles can retain old hair shafts for long periods of time, eliminating the need for continuous regeneration to maintain hair coat integrity. Working against that goal are anagen-spreading waves, carrying high levels of activating signals to telogen follicles. To balance between resisting anagen-spreading waves for a minimal period of time and efficiently responding to them thereafter, a protection mechanism has developed. It renders hair follicles refractory to anagen-activating signals during early telogen and sensitive to the same signals during late telogen, yet dormant in their absence.

      Timing refractory telogen

      At the heart of the telogen refractivity mechanism is a signaling threshold switch operating in the dermal macroenvironment (Figure 1). In mice, the refractory-to-competent transition occurs after about 1 month in telogen and is accompanied by a precipitous drop in the expression of Bmp2/4 ligands (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ) and Dkk1/Sfrp4 WNT antagonists (
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ) in the dermis and cutaneous adipocytes. This macroenvironmental switch is aided by the intrafollicular switch operating, at a minimum, across the BMP, WNT, and fibroblast growth factor (Fgf)7→Fgfr2-IIIb signaling pathways (
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ). Once these switches have occurred, competent telogen hair follicles are on the verge of an anagen transition. With inhibitory BMP signaling largely eliminated and the number of WNT antagonists dwindled, a transient rise in WNT ligands may surpass the signaling threshold and induce the onset of anagen. Curiously, despite this delicate signaling equilibrium during competent telogen, spontaneous WNT activation events are quite rare. In fact, they are so rare in mice that competent telogen can last for several months (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ,
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ).
      The refractory-to-competent signaling threshold switch works to a large extent at the level of ligands and antagonists. For example, competent telogen follicles can be turned refractory again simply by adding more Bmp4, and normal refractory telogen can be cut short by overexpressing the soluble BMP antagonist noggin (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ). Changes in the response patterns by bulge and hair germ progenitors via changes in receptor and transcription factor profiles constitute an additional component of the mechanisms underlying this switch (
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      ; Geyfman et al., 2011;
      • Oshimori N.
      • Fuchs E.
      Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
      ). It is important to note that, although the role of macroenvironmental signaling in maintaining refractory telogen is clear, the mechanism that regulates gene expression changes in the dermis and cutaneous adipocytes after a predefined period of time is not known.

      Discovering new “gears” in the hair cycle clock

      Given the complexity of hair follicles, it is reasonable to expect that the hair cycle clock might display redundant features, such as overlapping regulation of the same event by several signaling pathways. Such redundancy would enable hair follicles to more reliably sort out true signals from signaling noise and to adapt more efficiently their regeneration dynamics to changing environmental conditions. Indeed, in this issue,
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      provide compelling evidence for the key role of Fgf18 signaling in maintaining telogen refractivity. The authors show that in telogen follicles Fgf18 is preferentially expressed by bulge cells and to a lesser extent by hair germ cells and dermal papilla cells. Upon epithelial Fgf18 deletion, the telogen phase shortens from 1 month to just 1 week. These mutant mice display a fast hair cycling phenotype, closely reminiscent of that in K14-Noggin mice, in which noggin overexpression reduces BMP-mediated telogen refractivity (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ). This suggests that Fgf18 and BMPs act in parallel as redundant regulators of refractory telogen. The fact that disruption of each of these signaling pathways is equally successful in eliminating refractive properties hints at signaling interdependence, the details of which are not fully understood.
      The inhibitory effect of Fgf18 on hair follicle regeneration was independently suggested in earlier studies.
      • Blanpain C.
      • Lowry W.E.
      • Geoghegan A.
      • et al.
      Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.
      ,
      • Greco V.
      • Chen T.
      • Rendl M.
      • et al.
      A two-step mechanism for stem cell activation during hair regeneration.
      , and
      • Hsu Y.C.
      • Pasolli H.A.
      • Fuchs E.
      Dynamics between stem cells, niche, and progeny in the hair follicle.
      showed that Fgf18 is indeed enriched in keratin 6–positive bulge cells and in the dermal papillae of telogen hair follicles, and that it exerts an antiproliferative effect on keratinocytes in vitro.
      • Hsu Y.C.
      • Pasolli H.A.
      • Fuchs E.
      Dynamics between stem cells, niche, and progeny in the hair follicle.
      also showed that specific ablation of Fgf18high keratin 6–positive bulge cells results in precocious anagen initiation, the phenotype that can be rescued by exogenous Fgf18 administration. The report by
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      provides important in vivo evidence that Fgf18 regulates the hair cycle clock, and it lays groundwork for further inquiries into the mechanism of telogen refractivity.
      A recent study by
      • Oshimori N.
      • Fuchs E.
      Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
      uncovered the essential role of transforming growth factor (Tgf)-β2 signaling in counterbalancing BMP-mediated telogen refractivity. In hair follicles, Tgf-β2 is secreted by dermal papillae during the competent telogen phase, which is accompanied by transient activation of phospho-Smad2/3 signaling in hair germ progenitors. This paracrine Tgf-β2 signaling is central to the normal anagen initiation mechanism because epithelial-specific ablation of the TGF-β pathway greatly extends telogen duration whereas administration of recombinant Tgf-β2 results in precocious anagen initiation. Interestingly,
      • Oshimori N.
      • Fuchs E.
      Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
      showed that the activating role of Tgf-β2 in the hair cycle is mediated by its direct antagonistic effect on BMP signaling in hair germ progenitors. Tmeff1, the direct transcriptional target of the TGF-β pathway, dampens canonical BMP→phospho-Smad1/5/8 signaling in hair germ cells. Small hairpin RNA–mediated deletion of Tmeff1 is sufficient to replicate the delayed anagen initiation phenotype of TGF-β signaling–deficient mice. In this respect, it is tempting to speculate that TGF-β signaling is also at the base of the well-known phenomenon of wounding-induced hair regeneration. Tgf-βs are among the key mediators of the wound-healing process, released by multiple cell types in the wound macroenvironment, including macrophages, mast cells, platelets, and fibroblasts. It is plausible that the transient rise in these macroenvironmental Tgf-βs simulates the effect of intrafollicular Tgf-β2 on hair germ cells and induces anagen initiation at the wound edges.

      New tools in the hair research toolbox

      Experimental assessment of telogen refractivity is challenging. Standard experimental techniques (such as histological hair cycle analysis at early postnatal time points or after hair plucking in adult animals) can be inadequate. Telogen phenotypes often do not become apparent until after the third hair cycle, and plucking-induced hair regeneration likely involves additional mechanisms that are not present during spontaneous physiological regeneration. There are, however, experimental techniques that can be adopted by almost any laboratory. Long-term hair growth pattern analysis is highly informative in evaluating the adult hair cycle. Skin pigmentation patterns resulting from anagen-coupled melanogenesis can be photographically recorded from a single animal over a prolonged period of time (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ). Temporal analysis of such patterns can reveal even subtle telogen timing defects. For example, consistent shortening of telogen to less than 1 month and simplification of hair growth patterns indicate defects in refractory telogen. Competent telogen length is normally highly variable, ranging from 1 day to many months, whereas decreased variability of this phase and increased asymmetry of hair growth patterns suggest enhanced spontaneous anagen initiation.
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      adopt this technique elegantly and show that a refractory telogen defect in epithelial Fgf18-null mice manifests itself clearly in highly dynamic and symmetric wave-like hair growth patterns (see Figure 3 of their article).
      Additional experimental techniques include the quantitative hair plucking assay (i.e., timing regenerative response following hair plucking from a group of just 50 or 200 telogen follicles), expression analysis on longitudinal skin strips spanning several adjacent hair growth domains, transgenic skin transplantation, and intradermal protein administration assays (
      • Plikus M.V.
      • Mayer J.A.
      • de la Cruz D.
      • et al.
      Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
      ). Caution must be exercised, however, in designing and interpreting the results of such experiments. Anagen can be induced artificially during highly responsive, competent telogen as a result of manipulations such as unintentional micro-wounding upon animal handling. In fact,
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      were not able to validate the anagen-inducing effect of Fgf18 protein reported earlier by the same group (
      • Kawano M.
      • Komi-Kuramochi A.
      • Asada M.
      • et al.
      Comprehensive analysis of FGF and FGFR expression in skin: FGF18 is highly expressed in hair follicles and capable of inducing anagen from telogen stage hair follicles.
      ). Upon further careful experimentation,
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      conclude that the hair growth–promoting effect of Fgf18, which contradicts its inhibitory role in the hair cycle, was likely indirect, resulting from experimental manipulations.

      New targets in hair loss treatment

      The lack of coupling between human scalp hair follicles contributes to hair growth pathology. Because anagen in the scalp lasts for several years in humans, the majority of normal scalp hair follicles are growing at any given time, even if they rely only on rare intrinsic anagen initiation. In androgenic alopecia, the anagen phase shortens substantially, whereas intrinsic anagen initiation does not become more efficient. With the telogen-to-anagen length ratio now altered in favor of telogen, there is a much larger proportion of telogen hair follicles at any given time. Thus, the human scalp skin appears bald because scalp follicles do not retain old hair shafts efficiently as compared with mouse pelage follicles. An attractive method for anti–hair-loss therapy would be reactivating the coupling between scalp hair follicles (reviewed in
      • Plikus M.V.
      • Baker R.E.
      • Chen C.C.
      • et al.
      Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
      ) so that rare spontaneous activation events can spread, increasing the overall number of follicles in anagen. An alternative method would be counteracting intrafollicular telogen refractivity, and in this respect Fgf18 and TGF-β signaling emerge as potential targets. For example, further inquiries into the Fgf18→Fgfr3/4 pathway are encouraged by the fact that Fgf18 is indeed elevated in the epithelial progenitor cells of human hair follicles (
      • Garza L.A.
      • Yang C.C.
      • Zhao T.
      • et al.
      Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
      ). In addition, soluble Fgfr3/4 extracellular domain fragments promote hair growth in mice upon local and systemic delivery (
      • Brennan T.
      • Dean R.
      • Kavanaugh W.M.
      • et al.
      Hair growth methods using Fgfr4 extracellular domains.
      ,
      • Brennan T.
      • Dean R.
      • Kavanaugh W.M.
      • et al.
      Hair growth methods using Fgfr3 extracellular domains.
      ).
      In summary,
      • Kimura-Ueki M.
      • Oda Y.
      • Oki J.
      • et al.
      Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
      and
      • Oshimori N.
      • Fuchs E.
      Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
      add Fgf18 and Tgf-β2 firmly to the list of crucial hair cycle clock regulators. Future studies should aim to establish details of how the BMP, WNT, FGF, TGF-β, and other signaling pathways jointly regulate refractory telogen, competent telogen, and telogen-to-anagen initiation events within each hair follicle stem cell niche and throughout the skin (Figure 1).

      ACKNOWLEDGMENTS

      The author wishes to thank Dr Cheng-Ming Chuong for helpful discussions and suggestions.

      REFERENCES

        • Blanpain C.
        • Lowry W.E.
        • Geoghegan A.
        • et al.
        Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.
        Cell. 2004; 118: 635-648
        • Botchkarev V.A.
        • Botchkareva N.V.
        • Nakamura M.
        • et al.
        Noggin is required for induction of the hair follicle growth phase in postnatal skin.
        FASEB J. 2001; 15: 2205-2214
        • Brennan T.
        • Dean R.
        • Kavanaugh W.M.
        • et al.
        Hair growth methods using Fgfr4 extracellular domains.
        WIPO patent application WO/2011/034940. 2011
        • Brennan T.
        • Dean R.
        • Kavanaugh W.M.
        • et al.
        Hair growth methods using Fgfr3 extracellular domains.
        WIPO patent application WO/2011/084711. 2011
        • Enshell-Seijffers D.
        • Lindon C.
        • Kashiwagi M.
        • et al.
        β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair.
        Dev Cell. 2010; 18: 633-642
        • Festa E.
        • Fretz J.
        • Berry R.
        • et al.
        Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.
        Cell. 2011; 146: 761-771
        • Garza L.A.
        • Yang C.C.
        • Zhao T.
        • et al.
        Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
        J Clin Invest. 2011; 121: 613-622
        • Geyfman M.
        • Gordon W.
        • Paus R.
        • et al.
        Identification of telogen markers underscores that telogen is far from a quiescent hair cycle phase.
        J Invest Dermatol. 2012; 132: 721-724
        • Greco V.
        • Chen T.
        • Rendl M.
        • et al.
        A two-step mechanism for stem cell activation during hair regeneration.
        Cell Stem Cell. 2009; 4: 155-169
        • Hsu Y.C.
        • Pasolli H.A.
        • Fuchs E.
        Dynamics between stem cells, niche, and progeny in the hair follicle.
        Cell. 2011; 144: 92-105
        • Kawano M.
        • Komi-Kuramochi A.
        • Asada M.
        • et al.
        Comprehensive analysis of FGF and FGFR expression in skin: FGF18 is highly expressed in hair follicles and capable of inducing anagen from telogen stage hair follicles.
        J Invest Dermatol. 2005; 124: 877-885
        • Kimura-Ueki M.
        • Oda Y.
        • Oki J.
        • et al.
        Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling.
        J Invest Dermatol. 2012; 132: 1338-1345
        • Lowry W.E.
        • Blanpain C.
        • Nowak J.A.
        • et al.
        Defining the impact of beta-catenin/Tcf transactivation on epithelial stem cells.
        Genes Dev. 2005; 19: 1596-1611
        • Oshimori N.
        • Fuchs E.
        Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
        Cell Stem Cell. 2012; 10: 63-75
        • Plikus M.V.
        • Baker R.E.
        • Chen C.C.
        • et al.
        Self-organizing and stochastic behaviors during the regeneration of hair stem cells.
        Science. 2011; 332: 586-589
        • Plikus M.V.
        • Mayer J.A.
        • de la Cruz D.
        • et al.
        Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
        Nature. 2008; 451: 340-344