Hair growth
Cyclical changes in rat vibrissa follicles maintained In vitro.

Philpott MP, Kealey T.

Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. m.p.philpott qmw.ac.uk

In mammals hair growth is cyclical; however, the factors that regulate the hair growth cycle are still poorly understood. The recent development of methods for culturing hair follicles in vitro has proved an important tool to investigate many aspects of the regulation of hair follicle growth. At present, however, these models are based on the culture of anagen hair follicles and have only partially been used to address the cyclical nature of hair growth. In this study we have made use of the fact that in rodents the hair growth cycle is synchronized, well characterized, and relatively short. We have isolated vibrissa follicles from 12 d old rats and confirmed by histology that these follicles are in the anagen stage of their first hair growth cycle. We have then maintained these follicles in vitro, on Gelfoam supports, for up to 23 d (35 d of age) and compared their histology with in vivo follicles from equivalent age littermates. We observed that 12 d old follicles maintained in vitro for up to 23 d show changes in morphology that suggest that cultured rat vibrissa follicles retain cyclical activity in vitro. Cyclical changes in hair follicle morphology were only seen in follicles maintained on gelfoam supports and moreover, hair follicle size appears to be a key feature in determining the ability of the follicle to cycle in vitro. All follicles that showed cyclical changes in vitro, however, appeared to remain blocked in pro-anagen. These data suggest that the vibrissa follicle is a in vitro good model system with which to investigate hair cycle control. J Invest Dermatol 115:1152-1155 2000

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Hair growth
Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.

Peters EM, Botchkarev VA, Botchkareva NV, Tobin DJ, Paus R.

Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Martinstr. 52, D-20246 Hamburg, Germany.

As the neuropeptide substance P can manipulate murine hair growth in vivo, we here further studied the role of sensory neuropeptides in hair follicle biology by determining the distribution and hair-cycle-dependent remodeling of the sensory innervation in C57BL/6 mouse back skin. Calcitonin-gene-related peptide, substance P, and peptide histidine methionine (employed as vasoactive intestinal peptide marker) were identified by immunohistochemistry. All of these markers immunolocalized to bundles of nerve fibers and to single nerve fibers, with distinct distribution patterns and major hair-cycle-associated changes. In the epidermis and around the distal hair follicle and the arrector pili muscle, only calcitonin-gene-related peptide immunoreactive nerve fibers were visualized, whereas substance P and peptide histidine methionine immunoreactive nerve fibers were largely restricted to the dermis and subcutis. Compared to telogen skin, the number of calcitonin-gene-related peptide, substance P, and peptide histidine methionine immunoreactive single nerve fibers increased significantly (p < 0.01) during anagen, including around the bulge region (the seat of epithelial stem cells). Substance P significantly accelerated anagen progression in murine skin organ culture, whereas calcitonin-gene-related peptide and a substance-P-inhibitory peptide inhibited anagen (p < 0.05). The inhibitory effect of calcitonin-gene-related peptide could be antagonized by coadministrating substance P. In contrast to substance P, calcitonin-gene-related peptide failed to induce anagen when released from subcutaneous implants. This might reflect a differential functional assignment of the neuropeptides calcitonin-gene-related peptide and substance P in hair growth control, and invites the use of neuropeptide receptor agonists and antagonists as novel pharmacologic tools for therapeutic hair growth manipulation.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11179999&dopt=Abstract alopecia, hair loss hair growth



Hair growth
Control of hair growth and follicle size by VEGF-mediated angiogenesis.

Yano K, Brown LF, Detmar M.

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.

The murine hair follicle undergoes pronounced cyclic expansion and regression, leading to rapidly changing demands for its vascular support. Our study aimed to quantify the cyclic changes of perifollicular vascularization and to characterize the biological role of VEGF for hair growth, angiogenesis, and follicle cycling. We found a significant increase in perifollicular vascularization during the growth phase (anagen) of the hair cycle, followed by regression of angiogenic blood vessels during the involution (catagen) and the resting (telogen) phase. Perifollicular angiogenesis was temporally and spatially correlated with upregulation of VEGF mRNA expression by follicular keratinocytes of the outer root sheath, but not by dermal papilla cells. Transgenic overexpression of VEGF in outer root sheath keratinocytes of hair follicles strongly induced perifollicular vascularization, resulting in accelerated hair regrowth after depilation and in increased size of hair follicles and hair shafts. Conversely, systemic treatment with a neutralizing anti-VEGF antibody led to hair growth retardation and reduced hair follicle size. No effects of VEGF treatment or VEGF blockade were observed in mouse vibrissa organ cultures, which lack a functional vascular system. These results identify VEGF as a major mediator of hair follicle growth and cycling and provide the first direct evidence that improved follicle vascularization promotes hair growth and increases hair follicle and hair size.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11181640&dopt=Abstract alopecia, hair loss hair growth



Hair growth
Hair growth pattern in nude mice.

Militzer K.

Central Animal Laboratory, University Clinics, Essen, Germany. klaus.militzer uni-essen.de

Nude mice are not bald but instead show an 'abortive' reduced hair growth on different sites of the integument. An albino (NMRI-nu) and a pigmented (C57BL/6-nu) strain of nude mice were examined as to whether the regional distribution pattern of this anagen hair proliferation is subject to the same ontogenetic development as in hairy mice. Hairy mice of both strains served as a comparison. Hair distribution was documented macroscopically by drawing and photography in a total of 415 mice of both sexes up to 421 days of age. Because of the pigmentation of the growing anagen hair follicles, the growth areas in the pigmented nude mice were distinctly visible whereas in the albino mice they were roughly recognisable from the boundaries of hair covering. The regional distribution of the 'abortive' anagen hair pattern in both nude strains corresponded to the wave-like course of the adult hair generations of hairy mice. As in older hairy mice, the hair cycle duration in nude mice was prolonged from an age of 121-180 days, the hair growth areas appeared reduced and less symmetrically orientated. Differences of up to 33% in body mass between the lighter nude and +/nu mice made ontogenetic comparison impossible so that all information is based on direct pattern or age comparison. The significance of experiments on the skin and hair follicles of nude mice is further increased if litters are examined comparatively and the temporal and spatial dimension of the follicle proliferation is considered more carefully than has been the case until now.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11275695&dopt=Abstract alopecia, hair loss hair growth



Hair growth
Contrasting localization of c-Myc with other Myc superfamily transcription factors in the human hair follicle and during the hair growth cycle.

Bull JJ, Muller-Rover S, Patel SV, Chronnell CM, McKay IA, Philpott MP.

Center for Cutaneous Research, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK. j.j.bull mds.qmw.ac.uk

The mammalian hair follicle is a highly dynamic skin appendage that undergoes repeated cycles of growth and regression, involving closely co-ordinated regulation of cell proliferation, differentiation, and apoptosis. The Myc superfamily of transcription factors have been strongly implicated in the regulation of these processes in many tissues. Using immunohistochemistry, we have investigated the patterns of c-Myc, N-Myc, Max, and Mad1-4 expression at different stages of the human hair growth cycle. N-Myc, Max, Mad1, and Mad3 immunoreactivity was detected in the epidermis and the epithelium of both anagen and telogen hair follicles. Three distinct patterns of hair follicle c-Myc immunoreactivity were observed. In the infundibulum, c-Myc staining was predominantly in the basal layers, with little detectable immunoreactivity in the terminally differentiating suprabasal layers; this pattern was similar to that seen in the epidermis. In contrast, c-Myc expression in the follicle bulb was found both in the proliferating germinative epithelial cells and in the terminally differentiating matrix cells that give rise to the hair fiber. Finally, intense c-Myc immunoreactivity was detected in the bulge region of the outer root sheath. Using the C8/144B antibody as a bulge marker, we confirmed that c-Myc immunoreactivity in the outer root sheath correlates with the putative hair follicle stem cell compartment. c-Myc expression in the bulge was independent of the hair growth cycle stage. Our data suggest that Myc superfamily members serve different functions in separate epithelial compartments of the hair follicle and may play an important role in determining cell fate within the putative stem cell compartment.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11286633&dopt=Abstract alopecia, hair loss hair growth



Hair growth
Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.

Craven AJ, Ormandy CJ, Robertson FG, Wilkins RJ, Kelly PA, Nixon AJ, Pearson AJ.

New Zealand Pastoral Agriculture Research Institute, Hamilton 2020, New Zealand. cravent agresearch.cri.nz

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.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11356702&dopt=Abstract alopecia, hair loss hair growth



Hair growth
Androgen responsive genes as they affect hair growth.

Sawaya ME, Keane RW, Blume-Peytavi U, Mullins DL, Nusbaum BP, Whiting D, Nicholson DW.

ARATEC Research PO Box 7, Ocala, FL 34478, USA. Aratec worldnet.att.net

Finasteride has been shown to be an effective treatment for men with androgenetic alopecia (AGA) as it restores hair growth to miniaturized hair follicles on the top of the scalp [1]. Caspases are regulators of programmed cell death, and very likely some specific caspases may function as mediators of the hair growth cycle. It is unclear whether finasteride influences the regulation of apoptosis via caspases in the hair follicle. Very little information is available regarding the role of caspases present in human hair follicles in normal scalp and in androgenetic alopecia. In this study we have analyzed the family of caspases, 1-10 along with usurpin, and XIAP, in men with normal scalp and in men with androgenetic alopecia before and after 6 months treatment with 1 mg oral finasteride treatment. Caspases 1, 3, 8 and 9 were detected predominantly within the isthmic and infundibular hair follicle area for both normal and AGA patients, however the expression of all factors, especially caspase 3 was greater in the AGA group than in the normal scalp group. AGA men had the same caspase factors but with greater expression. In the same AGA men treated with finasteride for 6 months, the expression of these factors was similar to levels in the normal group. Results from our study indicate caspase 3 to be of primary importance in normal hair homeostasis and that DHT may be signaling greater expression of caspases, inducing apoptosis in androgenetic alopecia. In conclusion, DHT may selectively regulate the caspase genes which play an important role in signaling programmed cell death, affecting the hair growth cycle.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11399535&dopt=Abstract alopecia, hair loss hair growth