Follicle Growth Cycle Research Articles

Follicle tracking under ultrasound revealed ovulation defects in unexplained infertility during natural cycle

Unexplained infertility (UI) was thought to have normal ovulation. To investigate if this is true, ovulation status of UI women were monitored by transvaginal ultrasonography (TVU) during natural cycle. Prospective study. 567 UI women diagnosed with basic infertility evaluation were enrolled to have TVU follicle tracking at an academic fertility center. Their menstrual cycle lengths were 26 to 30 days. The entire follicle development was monitored from day 10 of the cycle to the time of follicle rupture or to day 20 of the cycle. Follicle size was measured and recorded. 421 out of 567 UI women finished 629 natural cycles follicle tracking. In addition to normal follicle size ovulation, three types of abnormal follicular development were observed: 1) no follicular growth in 28 cycles (4.5%); 2) ovulation with small follicles (OSF, follicle ovulate at the size ≤16 mm) in 65 cycles (10.3%); and 3) luteinized unruptured follicles (LUF) in 34 cycles (5.4%). A total of 127 abnormal ovulation cycles were observed in this study, accounting for 20.2% of 629 UI cycles. Based on follicle tracking and timed intercourse, in 502 normal follicle size ovulation cycles 74 women became pregnant while in 65 OSF cycles only 2 became pregnant. The pregnancy rate was 14.7% vs 3.1% (P < 0.01). There was no pregnancy in the 34 LUF and 28 no follicle growth cycle. This study shows ovulation dysfunction existed in UI patients. TVU Follicle tracking is a reliable way to monitor follicle development and ovulation. One cycle of TVU to evaluate ovulation status will make the UI diagnosis more precise.

Cyclosporine A increases hair follicle growth by suppressing apoptosis-inducing factor nuclear translocation: a new mechanism.

Cyclosporine A (CsA) enhances hair growth through caspase-dependent pathways by retarding anagen-to-catagen phase transition in the hair follicle growth cycle. Whether apoptosis-inducing factor (AIF), a protein that induces caspase-independent apoptosis, can regulate the hair follicle cycle in response to CsA is currently unclear. Here, we show that the pro-hair growth properties of CsA are in part due to blockage of AIF nuclear translocation. We first isolate hair follicles from murine dorsal skin. We then used Western blot, immunohistochemistry and immunofluorescence to evaluate the expression and localization of AIF in hair follicles. We also determined whether modulation of AIF was responsible for the effects of CsA at the anagen-to-catagen transition. AIF was expressed in hair follicles during the anagen, catagen and telogen phases. There was significant nuclear translocation of AIF as hair follicles transitioned from anagen to late catagen phase; this was inhibited by CsA, likely due to reduced cyclophilin A expression and attenuated AIF release from mitochondria. However, we note that AIF translocation was not completely eliminated, which likely explains why the transition to catagen phase was severely retarded by CsA, rather than being completely inhibited. We speculate that blockade of the AIF signalling pathway is a critical event required for CsA-dependent promotion of hair growth in mice. The study of AIF-related signalling pathways may provide insight into hair diseases and suggest potential novel therapeutic strategies.

Derivation of hair-inducing cell from human pluripotent stem cells.

Dermal Papillae (DP) is a unique population of mesenchymal cells that was shown to regulate hair follicle formation and growth cycle. During development most DP cells are derived from mesoderm, however, functionally equivalent DP cells of cephalic hairs originate from Neural Crest (NC). Here we directed human embryonic stem cells (hESCs) to generate first NC cells and then hair-inducing DP-like cells in culture. We showed that hESC-derived DP-like cells (hESC-DPs) express markers typically found in adult human DP cells (e.g. p-75, nestin, versican, SMA, alkaline phosphatase) and are able to induce hair follicle formation when transplanted under the skin of immunodeficient NUDE mice. Engineered to express GFP, hESC-derived DP-like cells incorporate into DP of newly formed hair follicles and express appropriate markers. We demonstrated that BMP signaling is critical for hESC-DP derivation since BMP inhibitor dorsomorphin completely eliminated hair-inducing activity from hESC-DP cultures. DP cells were proposed as the cell-based treatment for hair loss diseases. Unfortunately human DP cells are not suitable for this purpose because they cannot be obtained in necessary amounts and rapidly loose their ability to induce hair follicle formation when cultured. In this context derivation of functional hESC-DP cells capable of inducing a robust hair growth for the first time shown here can become an important finding for the biomedical science.

Molecular cloning, characterization, and expression of sheep FGF5 gene

The fibroblast growth factor 5 gene (FGF5) is a member of the FGF gene family, and represents a candidate gene for hair length because of its role in the regulation of the hair follicle growth cycle. In our current study, we cloned, sequenced, and characterized the full-length FGF5 cDNA of Chinese Merino sheep. We obtained the complete genomic sequence of the FGF5 gene from sheep blood samples, and compared it to other FGF5 sequences in GenBank. We found that the FGF5 gene spanned 21,743bp of genomic DNA, and consisted of 3 exons and 2 introns, both of which differed from those of a previously annotated FGF5 genomic sequence from sheep. We also identified a previously undescribed FGF5 mRNA splicing variant, FGF5S, and the western blot analysis showed that the molecular weights of the FGF5 (34kDa) and FGF5s (17kDa) proteins were consistent with the estimates based on the genomic and cDNA sequence data. We examined the expression of both FGF5 mRNAs in various tissues of sheep, and found that the expression of the FGF5S mRNA was restricted to the brain, spleen, and skin tissue. The single-nucleotide polymorphism analysis of the genomic sequence revealed 72 genetic variants of the FGF5 gene. Our findings provide insight into the functions of the FGF5 gene in Chinese Merino.

Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors.

It has long been recognized that the hair follicle growth cycle and oscillation in the thickness of the underlying adipocyte layer are synchronized. Although factors secreted by adipocytes are known to regulate the hair growth cycle, it is unclear whether the epidermis can regulate adipogenesis. We show that inhibition of epidermal Wnt/β-catenin signaling reduced adipocyte differentiation in developing and adult mouse dermis. Conversely, ectopic activation of epidermal Wnt signaling promoted adipocyte differentiation and hair growth. When the Wnt pathway was activated in the embryonic epidermis, there was a dramatic and premature increase in adipocytes in the absence of hair follicle formation, demonstrating that Wnt activation, rather than mature hair follicles, is required for adipocyte generation. Epidermal and dermal gene expression profiling identified keratinocyte-derived adipogenic factors that are induced by β-catenin activation. Wnt/β-catenin signaling-dependent secreted factors from keratinocytes promoted adipocyte differentiation in vitro, and we identified ligands for the bone morphogenetic protein and insulin pathways as proadipogenic factors. Our results indicate epidermal Wnt/β-catenin as a critical initiator of a signaling cascade that induces adipogenesis and highlight the role of epidermal Wnt signaling in synchronizing adipocyte differentiation with the hair growth cycle.

Transcriptome sequencing reveals differences between anagen and telogen secondary hair follicle-derived dermal papilla cells of the Cashmere goat (Capra hircus)

Dermal papilla is considered the control center of hair follicle growth and hair cycle. The secondary hair follicle (producing cashmere) growth cycle of the Cashmere goat (Capra hircus) is circannual, and each growth phase can be easily distinguished by its long duration. To identify gene expression patterns and differences of the dermal papilla cell (DPC) between the anagen and telogen phases, we established two DPC lines: ana-DPCs (DPCs derived from the anagen secondary hair follicle) and tel-DPCs (DPCs derived from the telogen secondary hair follicle). Compared with the ana-DPCs, the tel-DPCs lost the capacity to form cell aggregates and showed lower cell proliferation rate. Transcriptome sequencing revealed that 825 genes were differentially expressed by at least threefold between the two DPC lines. These genes were significantly enriched in cell cycle control, cell division, and chromosome partitioning from the Eukaryotic Orthologous Groups of proteins (KOG) database and in cell cycle, cell adhesion molecules, cytokine-cytokine receptor interaction, and p53 signaling pathway from the Kyoto Encyclopedia of Gene and Genomes (KEGG) database. Enrichment analyses revealed that in the middle of the telogen the DPCs of secondary hair follicles (SHFs) seemed on the one hand to promote the degeneration of SHFs and cessation of cashmere growth, while on the other hand to resist self-apoptosis and prepare for the regeneration or revivification of fully functional dermal papillae. These findings provide a better understanding of hair follicle growth and will be useful for identification of novel molecules associated with the control of hair growth cycle.

Development of the Mouse Dermal Adipose Layer Occurs Independently of Subcutaneous Adipose Tissue and Is Marked by Restricted Early Expression of FABP4

The laboratory mouse is a key animal model for studies of adipose biology, metabolism and disease, yet the developmental changes that occur in tissues and cells that become the adipose layer in mouse skin have received little attention. Moreover, the terminology around this adipose body is often confusing, as frequently no distinction is made between adipose tissue within the skin, and so called subcutaneous fat. Here adipocyte development in mouse dorsal skin was investigated from before birth to the end of the first hair follicle growth cycle. Using Oil Red O staining, immunohistochemistry, quantitative RT-PCR and TUNEL staining we confirmed previous observations of a close spatio-temporal link between hair follicle development and the process of adipogenesis. However, unlike previous studies, we observed that the skin adipose layer was created from cells within the lower dermis. By day 16 of embryonic development (e16) the lower dermis was demarcated from the upper dermal layer, and commitment to adipogenesis in the lower dermis was signalled by expression of FABP4, a marker of adipocyte differentiation. In mature mice the skin adipose layer is separated from underlying subcutaneous adipose tissue by the panniculus carnosus. We observed that the skin adipose tissue did not combine or intermix with subcutaneous adipose tissue at any developmental time point. By transplanting skin isolated from e14.5 mice (prior to the start of adipogenesis), under the kidney capsule of adult mice, we showed that skin adipose tissue develops independently and without influence from subcutaneous depots. This study has reinforced the developmental link between hair follicles and skin adipocyte biology. We argue that because skin adipocytes develop from cells within the dermis and independently from subcutaneous adipose tissue, that it is accurately termed dermal adipose tissue and that, in laboratory mice at least, it represents a separate adipose depot.

Modelling hair follicle growth dynamics as an excitable medium.

The hair follicle system represents a tractable model for the study of stem cell behaviour in regenerative adult epithelial tissue. However, although there are numerous spatial scales of observation (molecular, cellular, follicle and multi follicle), it is not yet clear what mechanisms underpin the follicle growth cycle. In this study we seek to address this problem by describing how the growth dynamics of a large population of follicles can be treated as a classical excitable medium. Defining caricature interactions at the molecular scale and treating a single follicle as a functional unit, a minimal model is proposed in which the follicle growth cycle is an emergent phenomenon. Expressions are derived, in terms of parameters representing molecular regulation, for the time spent in the different functional phases of the cycle, a formalism that allows the model to be directly compared with a previous cellular automaton model and experimental measurements made at the single follicle scale. A multi follicle model is constructed and numerical simulations are used to demonstrate excellent qualitative agreement with a range of experimental observations. Notably, the excitable medium equations exhibit a wider family of solutions than the previous work and we demonstrate how parameter changes representing altered molecular regulation can explain perturbed patterns in Wnt over-expression and BMP down-regulation mouse models. Further experimental scenarios that could be used to test the fundamental premise of the model are suggested. The key conclusion from our work is that positive and negative regulatory interactions between activators and inhibitors can give rise to a range of experimentally observed phenomena at the follicle and multi follicle spatial scales and, as such, could represent a core mechanism underlying hair follicle growth.

Progress in molecular genetics of hereditary alopecia/hypotrichosis

Hereditary alopecia/hypotrichosis is a large group of rare genetic disorders characterized by hair loss. Many causative genes and their corresponding chromosomal locations have been identified for several types of hereditary alopecia/hypotrichosis in recent years, including Marie-Unna hereditary hypotrichosis （U2HR, 8p21.3）, autosomal dominant hypotrichosis simplex （APCDD1, 18p11.22; RPL21, 13q12）, autosomal recessive hypotrichosis simplex （DSG4, 18q12.1; DSC3, 18q21.1; LIPH, 3q26-27; P2RY5, 13q13-14; 10q11.23-22.3; ？p21.3-p22.3）, autosomal recessive woolly hair/hypotrichosis （LIPH, 3q26-27; P2RYS, 13q13- 14）, autosomal dominant woolly hair/hypotrichosis （KRT74, 12q12-14） and ichthyosis follicularis-alopecia- photophobia syndrome （MBTPS2, Xp22）. These genes play critical roles in the regulation of hair follicle morphogenesis and growth cycles, and their pathogenic mutations may lead to abnormality in hair follicle morphogenesis and development, thus result in alopecia/hypotrichosis. Key words: Alopecia; Heredity; Molecular biology; Genes; Mutation

Effect of Helium-Neon Laser Irradiation on Hair Follicle Growth Cycle of Swiss Albino Mice

We report the results of a study carried out to investigate the effect of helium-neon (He-Ne) laser (632.8 nm) irradiation on the hair follicle growth cycle of testosterone-treated and untreated mice. Both histology and optical coherence tomography (OCT) were used for the measurement of hair follicle length and the relative percentage of hair follicles in different growth phases. A positive correlation (R = 0.96) was observed for the lengths of hair follicles measured by both methods. Further, the ratios of the lengths of hair follicles in the anagen and catagen phases obtained by both methods were nearly the same. However, the length of the hair follicles measured by both methods differed by a factor of 1.6, with histology showing smaller lengths. He-Ne laser irradiation (at ∼1 J/cm²) of the skin of both the control and the testosterone-treated mice was observed to lead to a significant increase (p < 0.05) in % anagen, indicating stimulation of hair growth. The study also demonstrates that OCT can be used to monitor the hair follicle growth cycle, and thus hair follicle disorders or treatment efficacy during alopecia.

Dlx3 is a crucial regulator of hair follicle differentiation and cycling

Dlx homeobox transcription factors regulate epidermal, neural and osteogenic cellular differentiation. Here, we demonstrate the central role of Dlx3 as a crucial transcriptional regulator of hair formation and regeneration. The selective ablation of Dlx3 in the epidermis results in complete alopecia owing to failure of the hair shaft and inner root sheath to form, which is caused by the abnormal differentiation of the cortex. Significantly, we elucidate the regulatory cascade that positions Dlx3 downstream of Wnt signaling and as an upstream regulator of other transcription factors that regulate hair follicle differentiation, such as Hoxc13 and Gata3. Colocalization of phospho-Smad1/5/8 and Dlx3 is consistent with a regulatory role for BMP signaling to Dlx3 during hair morphogenesis. Importantly, mutant catagen follicles undergo delayed regression and display persistent proliferation. Moreover, ablation of Dlx3 expression in the telogen bulge stem cells is associated with a loss of BMP signaling, precluding re-initiation of the hair follicle growth cycle. Taken together with hair follicle abnormalities in humans with Tricho-Dento-Osseous (TDO) syndrome, an autosomal dominant ectodermal dysplasia linked to mutations in the DLX3 gene, our results establish that Dlx3 is essential for hair morphogenesis, differentiation and cycling programs.

Dicer is required for maintenance of hair follicle stem cells in adult skin

Multiple miRNAs are expressed in developing and postnatal skin and hair follicles, and constitutive deletion of the miRNA processing enzyme Dicer in embryonic mouse skin causes failure of hair follicle morphogenesis and subsequent follicular degradation. To determine whether Dicer and miRNA functions are required in established hair follicles and epidermis in the adult mouse we generated Krt5-rtTA tetO-Cre Dicerfl/fl mice in which the Dicer gene can be inducibly deleted in the basal epidermis and hair follicle outer root sheath, including hair follicle stem cells, by dosage with oral doxycycline. Inducible Dicer deletion starting at postnatal day (P) 20, when hair follicles are just entering the first postnatal growth cycle, resulted in loss of external hair starting within 10days of doxycycline treatment. Induction of mutation during the resting stage of the hair follicle growth cycle did not immediately result in histological abnormalities or loss of hair. However, expression of the hair follicle bulge stem cell markers K15 and CD34 was lost soon after induction. Subsequent hair plucking stimulated a new cycle of hair follicle growth in control littermate, but not induced Dicer mutant skin. These results demonstrate a requirement for Dicer in maintaining the ability of adult hair follicles to grow and regenerate, and indicate that Dicer is required for maintenance of hair follicle epithelial stem cells.

Four Independent Mutations in the Feline Fibroblast Growth Factor 5 Gene Determine the Long-Haired Phenotype in Domestic Cats

To determine the genetic regulation of "hair length" in the domestic cat, a whole-genome scan was performed in a multigenerational pedigree in which the "long-haired" phenotype was segregating. The 2 markers that demonstrated the greatest linkage to the long-haired trait (log of the odds > or = 6) flanked an estimated 10-Mb region on cat chromosome B1 containing the Fibroblast Growth Factor 5 (FGF5) gene, a candidate gene implicated in regulating hair follicle growth cycle in other species. Sequence analyses of FGF5 in 26 cat breeds and 2 pedigrees of nonbreed cats revealed 4 separate mutations predicted to disrupt the biological activity of the FGF5 protein. Pedigree analyses demonstrated that different combinations of paired mutant FGF5 alleles segregated with the long-haired phenotype in an autosomal recessive manner. Association analyses of more than 380 genotyped breed and nonbreed cats were consistent with mutations in the FGF5 gene causing the long-haired phenotype in an autosomal recessive manner. In combination, these genomic approaches demonstrated that FGF5 is the major genetic determinant of hair length in the domestic cat.

Hormonal regulation of hair follicles exhibits a biological paradox

Hair's importance for insulation and camouflage or human communication means that hairs need to change with season, age or sexual development. Regular, regenerating hair follicle growth cycles produce new hairs which may differ in colour and/or size, e.g., beard development. Hormones of the pineal-hypothalamus-pituitary axis coordinate seasonal changes, while androgens regulate most sexual aspects with paradoxically different effects depending on body site; compare beard growth and balding! Hormones affect follicular mesenchymal-epithelial interactions altering growing time, dermal papilla size and dermal papilla cell, keratinocyte and melanocyte activity. Greater understanding of these mechanisms should improve treatments for poorly controlled hair disorders, alopecia and hirsutism.

Prolactin Signaling Influences the Timing Mechanism of the Hair Follicle: Analysis of Hair Growth Cycles in Prolactin Receptor Knockout Mice*

Pituitary PRL regulates seasonal hair follicle growth cycles in many mammals. Here we present the first evidence implicating PRL in the nonseasonal, wave-like pelage replacement of laboratory mice. In this study we show that messenger RNA transcripts encoding the one long and two short forms of PRL receptor are present in the skin of adult and neonate mice. The receptor protein was immunolocalized to the hair follicle as well as the epidermis and sebaceous glands. Furthermore, PRL messenger RNA was detected within skin extracts, suggesting a possible autocrine/paracrine role. Analysis of the hair growth phenotype of PRL gene-disrupted mice (PRLR(-/-)) revealed a change in the timing of hair cycling events. Although no hair follicle development differences were noted in PRLR(-/-) neonates, observations of the second generation of hair growth revealed PRLR(-/-) mice molted earlier than wild types (PRLR(+/+)). The advance was greater in females (29 days) than in males (4 days), resulting in the elimination of the sexual dimorphism associated with murine hair replacement. Heterozygotes were intermediate between PRLR(-/-) and PRLR(+/+) mice in molt onset. Once initiated, the pattern and progression of the molt across the body were similar in all genotypes. Although all fiber types were present and appeared structurally normal, PRLR(-/-) mice had slightly longer and coarser hair than wild types. These findings demonstrate that PRL has an inhibitory effect on murine hair cycle events. The pituitary PRL regulation of hair follicle cycles observed in seasonally responsive mammals may be a result of pituitary PRL interacting with a local regulatory mechanism.

Controls of hair follicle cycling.

Nearly 50 years ago, Chase published a review of hair cycling in which he detailed hair growth in the mouse and integrated hair biology with the biology of his day. In this review we have used Chase as our model and tried to put the adult hair follicle growth cycle in perspective. We have tried to sketch the adult hair follicle cycle, as we know it today and what needs to be known. Above all, we hope that this work will serve as an introduction to basic biologists who are looking for a defined biological system that illustrates many of the challenges of modern biology: cell differentiation, epithelial-mesenchymal interactions, stem cell biology, pattern formation, apoptosis, cell and organ growth cycles, and pigmentation. The most important theme in studying the cycling hair follicle is that the follicle is a regenerating system. By traversing the phases of the cycle (growth, regression, resting, shedding, then growth again), the follicle demonstrates the unusual ability to completely regenerate itself. The basis for this regeneration rests in the unique follicular epithelial and mesenchymal components and their interactions. Recently, some of the molecular signals making up these interactions have been defined. They involve gene families also found in other regenerating systems such as fibroblast growth factor, transforming growth factor-beta, Wnt pathway, Sonic hedgehog, neurotrophins, and homeobox. For the immediate future, our challenge is to define the molecular basis for hair follicle growth control, to regenerate a mature hair follicle in vitro from defined populations, and to offer real solutions to our patients' problems.

Effects of season on fleece traits of Angora does in the US

Twenty nonpregnant Angora does were used to determine seasonal effects on fleece traits, including fiber growth and follicle activity. Does grazed pastures and were supplemented with a 50% concentrate diet at a level near that required for BW maintenance. Clean fiber growth rate was greatest ( p<0.05) among seasons in summer and lowest ( p<0.05) in winter (1.13, 0.85, 0.98 and 1.20 mg/cm 2 per day for autumn, winter, spring and summer, respectively); seasonal differences in fiber diameter were similar (34.9, 31.7, 33.7 and 36.5 μm for autumn, winter, spring and summer, respectively). Fleece fiber medullation was greatest ( p<0.05) in summer (0.48, 0.32, 0.40 and 0.76%), and medullated fiber diameter was greater in spring and summer than winter (69, 65, 73 and 71 μm for autumn, winter, spring and summer, respectively). Primary follicle activity varied with season more than did activity of secondary follicles (primary: 74, 23, 79 and 99%; secondary: 97, 86, 94 and 99%; for autumn, winter, spring and summer, respectively). In summary, Angora goats in the US appear to exhibit seasonal follicle and fiber growth cycles, the knowledge of which may improve future nutritional management for efficient feed use in mohair production. The optimal time of shearing US Angoras for minimal contamination with medullated fibers may be just before spring and autumn equinoxes when it is likely that medullated fibers have been recently shed.

Identification of Differentially Expressed Genes During a Wool Follicle Growth Cycle Induced by Prolactin

The wool follicles of New Zealand Wiltshire sheep can be induced to undergo growth cycles by manipulating circulating prolactin levels. Altered patterns of gene expression through this cycle were examined using differential display, and nine sequence tags for differentially expressed genes were isolated. Four of these tags were identified as fragments of known genes, encoding a wool keratin, KRTAP3.2, a desmosome component, desmoglein 1, an epithelial cell marker, stratifin, and a protein kinase, Clk3. All four genes were shown to be downregulated in telogen skin compared with anagen. In situ hybridization showed that all had localization patterns which included cells that are absent in telogen. The stratifin tag was used to clone a cDNA that incorporated a complete open-reading frame for ovine stratifin. Ovine stratifin is similar to the human form, showing only six single residue differences in the predicted amino acid sequence. Stratifin probably acts as a regulator of other proteins involved in trichocyte cell cycling and differentiation. Clk3 is involved in regulating RNA splicing. KRTAP3.2 and Dsg1 both play structural roles in hair follicles. The other five tags, including two representing genes that were upregulated during catagen, could not be identified by homology. Differential display is an effective means of identifying genes involved in follicle function and, potentially, of genes controlling the growth cycle.

Hair Growth Cycle Affects Hair Follicle Destruction by Ruby Laser Pulses

It has been shown that normal mode ruby laser pulses (694 nm) are effective in selectively destroying brown or black pigmented hair follicles in adult Caucasians. This study investigated how the various stages of the hair follicle growth cycle influence follicle destruction by ruby laser treatment, using a model of predictable synchronous hair growth cycles in the infantile and adolescent mice. A range of ruby laser pulse fluences was delivered during different stages of the hair growth cycle, followed by histologic and gross observations of the injury and regrowth of hair. Actively growing and pigmented anagen stage hair follicles were sensitive to hair removal by normal mode ruby laser exposure, whereas catagen and telogen stage hair follicles were resistant to laser irradiation. Selective thermal injury to follicles was observed histologically, and hair regrowth was fluence dependent. In animals exposed during anagen, intermediate fluences induced nonscarring alopecia, whereas high fluences induced scarring alopecia. The findings of this study suggest treatment strategies for optimal laser hair removal.

A possible role for Langerhans cells in the removal of melanin from early catagen hair follicles.

Hair pigmentation is coupled to the hair follicle growth cycle. A common feature of catagen is the translocation of melanin from the matrix to the dermal papilla of the hair follicle. However, the mechanism whereby this pigment, not incorporated into the hair shaft, is removed from the hair bulb during early catagen is poorly understood. Routine ultrastructural examination of four normal scalp specimens revealed a rare hair follicle in early catagen. Close study of the hair bulb of this catagen follicle revealed a Langerhans cell in the process of transferring pigment from the matrix to the dermal papilla. This cell also contained numerous characteristic Langerhans granules (LG) (also known as Birbeck granules). Interestingly, these granules were intimately associated with melanosomes: so intimate, in fact, that melanosomes appeared to have been endocytosed by LG. This unique demonstration of removal of hair follicle melanin by Langerhans cells during early catagen and of pigment uptake by Langerhans cells by endocytosis into LG, suggests one way by which 'unused' pigment can be removed from the hair follicle during catagen.