Fig. 13.1
The structure of the hair follicle and the hair cycle. Fully grown anagen hair follicle extends deeper into subcutaneous fat. Anagen hair follicle is divided into five anatomical segments: infundibulum, isthmus, bulge, suprabulbar portion, and bulb. The suprabulbar (Sup) and the bulb regress by apoptosis in catagen phase. The bulge harbors stem cells and marks the bottom of telogen hair follicle
A full-grown anagen HF is split into five anatomical substructures: infundibulum (the epidermal surface, the sebaceous duct), isthmus (the sebaceous duct, the bulge), bulge, suprabulb (between the bulge and the bulb), and bulb [3, 11, 12] (Fig. 13.1). It is important to note that those HF segments differentially express a panel of cell surface markers which enable targeted cell isolation of individual segments in mice [10], however, such markers have not been established in human HF.
13.2.2 The Bulge Area Provides the Stem Cell Niche
Using a label-retaining cell technique, quiescent follicular keratinocyte stem cells were identified in the bulge area both in mouse and human HF [4, 14, 15]. Colony formation assay demonstrated that they possess high proliferative capacity [6, 15–17]. Lineage tracking experiments elucidated that bugle stem cells are indispensable for the maintenance of HF homeostasis and multipotent to regenerate the sebaceous gland and the epidermis, when the stem/progenitor cells maintaining those structures are damaged [7]. Keratin 15 (mouse and human) [14, 17], 19 (human) [18], alpha6-integrin (mouse) [6, 18], CD34 (mouse) [19], and CD200 (human) [15] have been used as preferential markers for bulge stem cells. Later studies elucidated that several cell populations marked by MTS24 [20], Lrig1 [21], Lgr5 [22] and 6 [23], and Gli1 [24] expression also possess stem cell capacities, represented by the potency to repopulate the pilosebaceous unit and the epidermis. A recent study uncovered that melanocyte stem cells also reside in the bulge area, just below the KC stem cell niche [25].
13.2.3 Hair Cycle and the Change in HF Structure
Cyclic self-renewal is intrinsic to HF [3, 11]. The hair cycle is composed of three major stages: anagen (growing phase), catagen (regression phase), and telogen (resting phase) [3, 11] (Fig. 13.1). In the anagen phase, the size of HF is at the maximum. All five HF segments can be observed and the matrix cells located over the dermal papilla actively proliferate to produce the hair shaft [3, 11]. When HF shifts into catagen, proximal portions below the bulge (transient portion) start to regress by apoptosis to leave the permanent portion of HF [3, 26] (Fig. 13.1). During this process, the dermal papilla is pulled up by regressing structure to be at the bottom of telogen HF [3, 26]. The duration of anagen or telogen is greatly different among species and anatomical locations, but that of catagen is short in common [3].
13.2.4 Dissimilarities Between Mouse and Human Hair Follicles
Mice pelage HFs have been predominantly used for the studies to dissect basic HF biology, whereas human scalp HFs have been preferentially utilized as materials for clinical/translational research. Thus, it is beneficial to recognize biological distinctiveness clearly between these major resources for HF investigation.
Except for their difference in size, the fundamental morphology and physiology of HFs are conserved between mice and humans [27]. Thus, mice HFs provide useful materials to dissect human HF biology to some extent. In mice, pelage HFs concertedly cycle in waves starting from head to tail, whereas human scalp HFs randomly cycle. Most mice pelage HFs stop growing when they reach their destined length and stay in telogen, in the same way as human pelage HFs do; in contrast, human scalp HFs continue to grow over several years [11, 26, 27]. In mice pelage HF, shedding of the hair shaft is often delayed and that produced in one hair cycle before remains over the next telogen, but this phenomenon is rarely seen in human scalp HFs [27]. The bulge can easily be recognized as a perturbation of the outer root sheath in anagen HFs and epithelial sac-like structure in telogen HFs, respectively, whereas it can hardly be distinguished in human anagen HFs morphologically [4, 11, 15, 28]. Some biochemical differences have been noted between mouse and human bulge. For instance, CD34, a commonly used cell surface marker for mouse bulge stem cells, is not upregulated in human bulge [15].
Understanding of those similarities and dissimilarities is indispensable for appropriate interpretation and application of mice data to human subjects.
13.3 Immunological Features of Respective Hair Follicle Compartments
13.3.1 The Infundibulum~the Isthmus
Various leukocyte subsets, including Langerhans cells (LCs) and CD4+ and CD8+ T cells, tend to accumulate around the infundibulum~isthmus , an anatomical frontline against external insults, including microorganisms [29–32].
When mouse infundibular and isthmus KCs of pelage telogen HFs were isolated by differential expression of cell surface markers Sca1 and EpCAM (infundibular KCs, Sca-1+EpCAMint; isthmus KCs, Sca-1– EpCAMhi), they were shown to express higher levels of CCL20, a CCR6 ligand and CCL2, a CCR2 ligand, respectively, compared to other HFKC subsets [10]. Similarly, gene expression analysis of microdissected human HF detected upregulation of CCL2 and CCL20 in the infundibulum [10]. CC-chemokine receptor 2 (CCR2) and CCR6 have been shown to be necessary to recruit LC and its precursors to the epidermis [10].
These findings support that HFs may chemoattract leukocytes to the infudibulum~isthmus area for immune surveillance/protection.
13.3.2 The Bulge
As bulge stem cells are indispensable for the maintenance of HF homeostasis, it is reasonable to speculate that the bulge area may be the most representative anatomical location protected by immune privilege (IP) within HF.
In line with this, the MHC class I molecule was found to be downregulated in the bulge, implying that CD8+ T-cell–mediated cytotoxic immune response less likely targets this area [9, 33] (Fig. 13.2). The immunosuppressive cytokines, transforming growth factor-β (TGFβ), and macrophage migration inhibitory factor (MIF) and other immunosuppressive factors, including α-melanocortin stimulating hormone (α-MSH) and indoleamine-pyrrole 2,3-dioxygenase (IDO) were reported to be upregulated in the bulge, supporting that the bulge is an IP site [33–35] (Fig. 13.2). However, further functional assessment of those molecules adopting bulge-specific ablation or forced expression is required to confirm their contribution to IP maintenance in the bulge area.
Fig. 13.2
Proposed mechanisms providing immune privilege to the bulge and the lower portion of the hair follicle. Downregulation of MHC molecules and upregulation of immunosuppressive factors may contribute to the maintenance of immune privilege in the bulge and the lower portion of the hair follicle
CD200, a glycoprotein suppressing immune activity of macrophages via CD200R was shown to be overrepresented in the bulge of human scalp HF and mice pelage HF at the protein and messenger RNA levels, respectively [15, 36, 37] (Fig. 13.2). Interestingly, when Cd200-/- CD57BL/6 mice skin was transplanted onto wild-type CD57BL/6 mice, lymphocytic cell infiltration was elicited in the grafted skin with resultant hair loss resembling scarring alopecia [38]. This observation implied that CD200 might contribute to the maintenance of IP in the bulge by preventing unnecessary lymphocytic inflammation. However, CD200R expression by T cells has not been convincingly demonstrated and the underlying mechanism of this observation needs to be elucidated.
In mice HF, suprabasilar bulge KCs marked by an anti-S1P1 antibody were shown to produce its ligand CCL8 in response to mechanical stress by tape-stripping, suggesting active protection of the stem cell niche by secreting immune-repulsive cytokines [10].
13.3.3 The Suprabulbar Portion~the Bulb
Similar to the bulge area, MHC class I antigen was shown to be minimally expressed in the suprabulbar~bulbar portion of HF, suggesting that this area is also immune privileged [9, 32] (Fig. 13.2). Expression of MHC class I polypeptide-related sequence A (MICA), the ligand NK-cell–activating receptor NKG2D, is suppressed as well, possibly enabling this area to avoid NK cell recognition [39]. In contrast, immunosuppressive factors α-MSH, insulin-like growth factor 1 (IGF1), and cortisol are produced in this portion of HF, which may contribute to the maintenance of IP [9, 34, 35] (Fig. 13.2). As described above, functional studies are necessary to conclude if differential expression of those molecules indeed lowers the risk of unwanted immune reaction to this area.
CCL1 and CCL8 expression was detected in the suprabulb and the infundibulum areas of human anagen HF [10]. In addition, CXCL4, CXCL9, and CXCL11, the chemokines that bind to CXCR3, were expressed with similar pattern. This finding is interesting as a possible role of CXCR3+ T cells in the development of alopecia areata (AA) , a condition characterized by peribulbar dense T-cell infiltration, has been suggested in recent studies [40, 41].
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