No / Hair pigmentation is controlled by tightly coordinated programs of melanin synthesis and involves signaling through the melanocortin type 1 receptor (MC-1R) that regulates the switch between pheomelanogenesis and eumelanogenesis. However, the involvement of other signaling systems, including the bone morphogenetic protein (BMP) pathway, in the control of hair pigmentation remains to be elucidated. To assess the effects of BMP signaling on hair pigmentation, transgenic mice overexpressing the BMP antagonist noggin (promoter: keratin 5) were generated. Whereas wild-type C3H/HeJ mice have a subapical yellow band on otherwise black dorsal hairs, K5-Noggin mice are characterized by the absence of a yellow band and near-black pigment in dorsal coat. Noggin overexpression is accompanied by strongly reduced levels of Agouti signal protein and enhanced expression of microphthalmia transcription factor in the midphase of the hair-growth cycle. Wild-type color in K5-Noggin mice is restored by administration of a synthetic MC-1R antagonist resulting in the reappearance of a subapical yellow band. BMP-4 stimulates the expression of Agouti transcripts and protein in primary epidermal keratinocytes, and BMP signaling positively regulates dermal papilla-specific enhancer of the Agouti gene in primary dermal fibroblasts. Taken together, these data suggests that BMP signaling controls the expression of Agouti protein in the hair follicle and provide evidence for interaction between BMP and MC-1R signaling pathways to modulate the balance between pheomelanogenesis and eumelanogenesis during hair growth.

No / The word ¿gerontology¿ is familiar to most of us as a term that captures the study of the social, psychological, and biological aspects of aging. However, its derivative ¿gerontobiology¿ as applied to the hair follicle is more concerned with the latter aspect ¿ the biology of aging in the hair follicle mini-organ. As with any complex multicellular tissue system, the hair follicle is prone to broadly similar underlying processes that determine the functional longevity of organs and tissues. No matter how complex the tissue system is, it will contain cells that eventually lose functionality, reproductive potential and will ultimately die. The hair follicle is somewhat unusual among mammalian tissues in that it is a veritable histologic mélange of multiple cell types (e.g., epithelial, mesenchymal and neuro-ectodermal) that function contemporaneously in all stages of their life histories e.g., stem cells, transit-amplifying cells, and terminally differentiating cells. Some of these interactive cell systems appear to be nonessential for overall hair follicle survival (e.g., melanocytes). However, strikingly graying hair follicles may grow even more vigorously than their pigmented predecessors. Moreover, the hair follicle is unique in the adult mammal in that it follows a tightly regulated script of multiple lifelong cycles of cellular birth, proliferation, differentiation, and death. Powerful evolutionary selection ensures that the hair follicle is, in the main, hardwired against significant aging-related loss of function, even after 12 or more decades of life ¿ although some would argue with this view, if only on purely cosmetic grounds. Processes underlying aging in general, e.g., oxidative damage, telomere shortening, age-relating deficiencies related to nuclear/mitochondrial DNA damage and repair as well as age-related reductions in the cells¿ energy supply, will all impact on whether some follicular cell subpopulations will enter cellular senescence. This chapter will focus on how gerontobiology of the hair follicle may impact on certain aspects of hair fiber phenotype.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on July 14, 2010). Includes bibliographical references.

Skin-derived precursors (SKPs) are multipotent dermal stem cells that reside within a hair follicle niche and that share properties with embryonic neural crest precursors. Here, we have asked whether SKPs and their endogenous dermal precursors originate from the neural crest or whether, like the dermis itself, they originate from multiple developmental origins. To do this, we used two different mouse Cre lines that allow us to perform lineage tracing: Wnt1-cre, which targets cells deriving from the neural crest, and Myf5-cre, which targets cells of a somite origin. By crossing these Cre lines to reporter mice, we show that the endogenous follicle-associated dermal precursors in the face derive from the neural crest, and those in the dorsal trunk derive from the somites, as do the SKPs they generate. Despite these different developmental origins, SKPs from these two locations are functionally similar, even with regard to their ability to differentiate into Schwann cells, a cell type only thought to be generated from the neural crest. Analysis of global gene expression using microarrays confirmed that facial and dorsal SKPs exhibit a very high degree of similarity, and that they are also very similar to SKPs derived from ventral dermis, which has a lateral plate origin. However, these developmentally distinct SKPs also retain differential expression of a small number of genes that reflect their developmental origins. Thus, an adult neural crest-like dermal precursor can be generated from a non-neural crest origin, a finding with broad implications for the many neuroendocrine cells in the body.

Skin-derived precursors (SKPs) are multipotent dermal stem cells that reside within a hair follicle niche and that share properties with embryonic neural crest precursors. Here, we have asked whether SKPs and their endogenous dermal precursors originate from the neural crest or whether, like the dermis itself, they originate from multiple developmental origins. To do this, we used two different mouse Cre lines that allow us to perform lineage tracing: Wnt1-cre, which targets cells deriving from the neural crest, and Myf5-cre, which targets cells of a somite origin. By crossing these Cre lines to reporter mice, we show that the endogenous follicle-associated dermal precursors in the face derive from the neural crest, and those in the dorsal trunk derive from the somites, as do the SKPs they generate. Despite these different developmental origins, SKPs from these two locations are functionally similar, even with regard to their ability to differentiate into Schwann cells, a cell type only thought to be generated from the neural crest. Analysis of global gene expression using microarrays confirmed that facial and dorsal SKPs exhibit a very high degree of similarity, and that they are also very similar to SKPs derived from ventral dermis, which has a lateral plate origin. However, these developmentally distinct SKPs also retain differential expression of a small number of genes that reflect their developmental origins. Thus, an adult neural crest-like dermal precursor can be generated from a non-neural crest origin, a finding with broad implications for the many neuroendocrine cells in the body.

No / We have previously shown that the ubiquitously expressed lysosomal cysteine protease, cathepsin L (CTSL), is essential for skin and hair follicle homeostasis. Here we examine the effect of CTSL deficiency on hair follicle development and cycling in ctsl-/- mice by light and electron microscopy, Ki67/terminal dUTP nick-end labeling, and trichohyalin immunofluorescence. Hair follicle morphogenesis in ctsl-/- mice was associated with several abnormalities. Defective terminal differentiation of keratinocytes occurred during the formation of the hair canal, resulting in disruption of hair shaft outgrowth. Both proliferation and apoptosis levels in keratinocytes and melanocytes were higher in ctsl-/- than in ctsl+/+ hair follicles. The development of the hair follicle pigmentary unit was disrupted by vacuolation of differentiating melanocytes. Hair cycling was also abnormal in ctsl-/- mice. Final stages of hair follicle morphogenesis and the induction of hair follicle cycling were retarded. Thereafter, these follicles exhibited a truncated resting phase (telogen) and a premature entry into the first growth phase. Further abnormalities of telogen development included the defective anchoring of club hairs in the skin, which resulted in their abnormal shedding. Melanocyte vacuolation was again apparent during the hair cycle-associated reconstruction of the hair pigmentary unit. A hallmark of these ctsl-/- mice was the severe disruption in the exiting of hair shafts to the skin surface. This was mostly because of a failure of the inner root sheath (keratinocyte layer next to the hair shaft) to fully desquamate. These changes resulted in a massive dilation of the hair canal and the abnormal routing of sebaceous gland products to the skin surface. In summary, this study suggests novel roles for cathepsin proteases in skin, hair, and pigment biology. Principal target tissues that may contain protein substrate(s) for this cysteine protease include the developing hair cone, inner root sheath, anchoring apparatus of the telogen club, and organelles of lysosomal origin (eg, melanosomes).

The Ectodysplasin/Ectodysplasin receptor (Eda/Edar) signalling pathway is critical during development for the formation of skin appendages. However, its roles during adulthood are only recently being elucidated. Adult appendages, such as hair follicles (HFs), are known to become activated to respond to cutaneous injury. However, the HF houses distinct cell populations that display differing capacities to participate and persist in re-epithelialisation. We show, contrary to previous findings, that the best-characterised stem cell (SC) niche within the HF (the bulge) does not respond to injury during the earliest stages of wound healing. We propose that bulge SCs are prevented from participating in early repair as a protection mechanism against tumourigenesis. Despite the bulge niche not participating in early repair, we found the upper HF outer root sheath (ORS) to respond rapidly to injury. Our investigation into the role of Eda/Edar signalling during wound healing revealed that activation of the pathway was able to specifically induce proliferation within this portion of the HF. We further demonstrate a number of roles for the Eda/Edar pathway during adult wound healing, including, surprisingly, influencing several wound responses within the dermis. Specifically, an absence of Eda/Edar signalling in Tabby mice results in delayed wound healing, whereas acute activation of the pathway in wild-type (WT) mice can stimulate re-epithelialisation and enhance wound repair. These effects also translate to a model of human wound healing, where activation of Eda/Edar signalling accelerates re-epithelialisation and increases peri-wound proliferation. RNA-seq analysis reveals diverse gene regulation in the presence/absence of Eda/Edar signalling. Overall, these findings suggest that manipulation of the Eda/Edar pathway may represent an attractive potential therapeutic for enhancement of wound repair, potentially through maximising the natural growth capacity of peri-wound HFs.

Yes / The cutaneous healing response has evolved to occur rapidly, in order to minimize infection and to re‐establish epithelial homeostasis. Rapid healing is achieved through complex coordination of multiple cell types, which importantly includes specific cell populations within the hair follicle (HF). Under physiological conditions, the epithelial compartments of HF and interfollicular epidermis remain discrete, with K15+ve bulge stem cells contributing progeny for HF reconstruction during the hair cycle and as a basis for hair shaft production during anagen. Only upon wounding do HF cells migrate from the follicle to contribute to the neo‐epidermis. However, the identity of the first‐responding cells, and in particular whether this process involves a direct contribution of K15+ve bulge cells to the early stage of epidermal wound repair remains unclear. Here we demonstrate that epidermal injury in murine skin does not induce bulge activation during early epidermal wound repair. Specifically, bulge cells of uninjured HFs neither proliferate nor appear to migrate out of the bulge niche upon epidermal wounding. In support of these observations, Diphtheria toxin‐mediated partial ablation of K15+ve bulge cells fails to delay wound healing. Our data suggest that bulge cells only respond to epidermal wounding during later stages of repair. We discuss that this response may have evolved as a protective safeguarding mechanism against bulge stem cell exhaust and tumorigenesis. / BBSRC.

Yes / Pattern Hair Loss (PHL) is a chronic regressive condition of the scalp, where follicular miniaturisation and decreased scalp hair coverage occurs in affected areas. In all PHL cases there is a measurable progressive shortening of the terminal hair growth duration, along with reduced linear growth rates. In both genders, PHL initially shows an increase in short telogen hairs ≤30mm in length, reflecting a cycle completion of under six months in affected terminal hair follicles. To understand the miniaturisation process, we re-examine the dynamics of miniaturisation and ask the question, 'why do miniaturised hair follicles resist treatment?' In the light of recent developments in relation to hair regeneration, we looked back in the older literature for helpful clues 'lost to time' and reprise a 1978 Hermann Pinkus observation of an array of elastin deposits beneath the dermal papilla following subsequent anagen/telogen transitions in male balding, originally described by Arao and Perkins who concluded that these changes provide a "morphologic marker of the entire biologic process in the balding scalp". Thus, we have reviewed the role of the elastin-like bodies in hair pathology and we propose that alterations in elastin architecture may contribute to the failure of vellus-like hair reverting back to their terminal status and may indicate a new area for therapeutic intervention.

miRNAs are important post-transcriptional regulators of gene expression which play vital roles in the arrays of physiological processes, including skin and hair follicle (HF) development. In this study, the role for miR-214 in the skin and HF development and their postnatal physiological regeneration was investigated. miR-214 exhibits discrete expression patterns in the epidermis and HF in developing and postnatal skin, and is highly expressed in the epithelial stem cells and their lineage-committed progenies. The effects of miR-214 on HF morphogenesis and cycle progression were evaluated by using doxycyclineinducible miR-214 transgenic mice (K14-rtTA/TRE-miR-214). Keratinocyte specific miR-214 overexpression during skin embryogenesis resulted in the partial inhibition of HF induction and formation of the HF reduced in size producing thinner hair. Overexpression of miR-214 in telogen skin caused retardation of the anagen progression and HF growth. Inhibitory effects of miR- 214 on HF development and cycling were associated with supressed activity of stem cells, reduced proliferation in the hair matrix, and altered differentiation. miR-214 induced complex changes in gene expression programs in keratinocytes, including inhibition of cyclins and cyclin-dependent kinases and several essential components of Wnt, Edar, Shh and Bmp signalling pathways, whereas β-catenin acts as a novel conserved miR-214 target. Indeed, the inhibitory effects of miR-214 on HF development were rescued by intracutaneous delivery of pharmacological Wnt activator. Thus, this study demonstrated that by targeting β-catenin and, therefore, interfering with Wnt signalling activity miR-214 may act as one of the upstream effectors of the signalling cascades which govern HF morphogenesis and cycling.