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Biomedical subjects

A G Messenger

Publications and source records attributed to A G Messenger.

At least 55 records · Page 3Linked to original sources
PubMed1994

Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene.

One of the most potent pro-inflammatory mediators is the early-acting cytokine interleukin-1. Its actions are regulated by a structurally related anti-inflammatory cytokine known as the interleukin-1 receptor antagonist. We have previously characterized a DNA polymorphism in this gene (IL-1rn) and have found associations between allele 2 and several chronic inflammatory diseases. In the present study, we tested the frequency of allele 2 of the IL-1rn gene in 90 patients with alopecia areata compared with 261 healthy controls. There was a significant association between allele 2 of the polymorphism and the severity of alopecia areata. The frequency of allele 2 increased from 24.1% in the control population to 25.9% in patchy alopecia areata, 36.1% in alopecia totalis, and 47.2% in alopecia universalis (p = 0.005). This severity association is similar to that found in other epithelial-related diseases, including inflammatory bowel disease, lichen sclerosus, and systemic lupus erythematosus.

Alleles↗
PubMed1994

Extracellular matrix derived from hair and skin fibroblasts stimulates human skin melanocyte tyrosinase activity.

There is indirect evidence that both skin and hair melanocytes are regulated by the activity of adjacent cells. In hair, the specialized fibroblasts (dermal papilla cells) appear to play a role in the regulation of hair growth. Hair pigmentation may relate to hair growth. In skin, melanocytes are located adjacent to the basement membrane zone. As far as we are aware, direct interactions of fibroblasts with melanocytes have not previously been investigated. Accordingly, the objective of this study was to develop co-culture conditions in which to investigate whether dermal fibroblasts from skin or hair could influence melanocyte differentiation. The influence of fibroblast-conditioned media, co-culture with fibroblasts, and fibroblast-derived extracellular matrix (ECM) on normal human skin melanocyte tyrosinase activity was examined. Fibroblasts from both skin and hair were capable of altering melanocyte morphology and significantly increasing tyrosinase activity when melanocytes were cultured in the absence, but not the presence, of the major proliferative drives. Although stimulation of tyrosinase activity was detectable with conditioned medium and co-culture with fibroblasts, the most striking result was obtained with the fibroblast-produced ECM which, on average, produced a four-fold increase in tyrosinase activity within 6 days. Thus, the study describes co-culture conditions in which the stimulatory effect of the fibroblast on melanocyte differentiation can be examined.

Cell Differentiation↗
PubMed1994

Androgen action in cultured dermal papilla cells from human hair follicles.

Androgens are major regulators of human hair growth with paradoxically different effects on hair follicles depending on their body site. They stimulate terminal growth in many regions including the face, have no effect on eyelashes, but may cause inhibition and balding on the scalp in genetically disposed individuals. How this occurs is unknown. However, androgens may act on the hair follicle via the cells of the dermal papilla; these would then influence the other cells of the hair follicle by altering the production of regulatory substances such as growth factors and/or extracellular matrix components. Therefore, primary lines of dermal papilla cells have been established from androgen-sensitive hair follicles, such as beard, and control, relatively androgen-independent, non-balding scalp cells and their mechanism of androgen action has been compared. Isolated beard dermal papillae were larger than those from scalp follicles. Although dermal papilla cells did not respond to in vitro androgens by alterations in growth, androgen-dependent dermal papilla cells contained higher levels of specific, low capacity, high affinity androgen receptors than non-balding scalp cells. The ability of the cells to metabolise testosterone to 5 alpha-dihydrotestosterone in culture also varied in parallel to that predicted from studies of hair growth in the 5 alpha-reductase deficiency syndrome. These results support the hypothesis that androgens act via the dermal papilla. They also show that dermal papilla cells retain differences in gene expression in culture which appear to correspond with their androgenic response in vivo. Further studies of such cells should help elucidate why bald men can grow beards!

Androgens↗
PubMed1993

Hormones and hair growth: variations in androgen receptor content of dermal papilla cells cultured from human and red deer (Cervus elaphus) hair follicles.

Many hair follicles produce different types of hair in response to environmental changes or the mammals age, that are translated to the follicle by hormones. Androgens cause many changes, such as transforming vellus follicles producing insignificant hairs on the face to terminal beard ones at puberty or the reverse on the scalp. In male red deer the breeding season rise in androgens causes the annual production of a mane on the neck that is lost during the spring. Because the dermal papilla situated at the base of the hair follicle is important in determining the type of hair produced, androgens may act via the dermal papilla. Therefore, primary cell lines of dermal papilla cells from human and red deer follicles with different responses to androgens have been established. Specific saturable androgen receptors were present in all human papilla cells examined, with higher levels in cells from androgen-dependent follicles, e.g., beard than in control, non-balding scalp cells. In preliminary investigations of red deer, androgen receptors were only present in cells derived from mane follicles and were undetectable in flank or spring neck follicles. These similar results from both species support the hypothesis that androgens are acting on hair follicles via the dermal papilla. They also suggest that dermal papilla cells are potentially useful models for investigating the mechanism of androgen action because cultured cells appear to retain differences that relate to the androgen responsiveness of their parent follicle. The red deer seems particularly interesting in view of the much shorter hair-growth cycle than human scalp or beard follicles.

Adult↗
PubMed1993

Cyclosporin A prolongs human hair growth in vitro.

We studied the effect of cyclosporin A on human hair growth using a recently described model in which isolated hair follicles are grown in vitro. Cyclosporin A had no effect on the rate of hair growth, but at 10(-7) M, a dose within the therapeutic blood range, it maintained hair growth for longer than control to give a 42% greater mean follicle elongation after 15 d (p < 0.05). Eighteen of 42 cyclosporin-treated follicles (43%) were still growing after 15 d compared with one of 42 control follicles (2%). These results suggest that the hypertrichotic action of cyclosporin A may be due to prolongation of the anagen phase of the hair-growth cycle.

Cyclosporine↗
PubMed1993

HLA and ICAM-1 expression in alopecia areata in vivo and in vitro: the role of cytokines.

To investigate the hypothesis that aberrant HLA and adhesion molecule expression in alopecia areata (AA) are secondary to local release of interferon-gamma (IFN-gamma) or other cytokines, we have studied HLA ABC, -DQ, -DR and ICAM-1 expression by immunohistochemistry, and compared patterns of expression in lesional tissue sections with those observed in hair follicles maintained in short-term organ culture, both from normal individuals and non-lesional sites in AA patients. The organ cultures were supplemented with IFN-gamma, tumour necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF), in a range of doses. In lesional AA tissue sections, there was close spatial correlation of ICAM-1 with HLA-DR; prominent staining being noted in the pre-cortical matrix and dermal papilla (DP) of lesional anagen follicles. In cultured follicles, dose-dependent induction of HLA class I, DR and ICAM-1 by IFN-gamma, and HLA class I and ICAM-1, but not HLA-DR, by TNF-alpha was observed in follicular epithelium, mainly in the outer root sheath (ORS). The findings in these cultures were the same in follicles derived from normal individuals and AA patients. Cytokine-induced patterns of HLA and ICAM-1 expression observed in vitro in cultured follicles differed significantly from those observed in vivo in lesional tissue sections. In particular, IFN-gamma failed to induce HLA-DR expression in the pre-cortical matrix and dermal papilla (DP), sites where this is usually observed in AA. The results suggest local cytokine release is not the sole determinant of aberrant HLA-DR expression in AA.

Alopecia Areata↗
PubMed1993

Differences in testosterone metabolism by beard and scalp hair follicle dermal papilla cells.

OBJECTIVE: Androgens have paradoxically different effects on hair follicles depending on body site, stimulating beard growth while inducing regression in some areas of the scalp. The mesenchyme derived dermal papilla at the base of the hair follicle regulates many aspects of the growth of follicular epithelium, and is probably the site of androgen action. Since 5 alpha-dihydrotestosterone is considered to be the active intracellular androgen in many target tissues and is required for some androgen-mediated hair growth, such androgen-sensitive cells should contain 5 alpha-reductase. This study was designed to investigate whether cultured human dermal papilla cells contain 5 alpha-reductase and whether the metabolic capacity varies with the body site of the follicle in line with the clinical picture. DESIGN: Testosterone metabolism in cultured dermal papilla cells from androgen sensitive beard follicles was compared with less androgen dependent non-balding scalp follicles. Primary cell cultures were established from follicles of 11 patients with normal hair growth. The cells were grown to confluence in 10-cm Petri dishes and incubated with 5 nM 3H-testosterone in serum-free medium for 2 hours. The cells and the culture medium were collected separately for individual analysis. MEASUREMENTS: Unlabelled carrier and 14C-marker steroids were added to both the cell and medium extracts before separation by thin-layer chromatography. The individual steroid identities were confirmed by recrystallizing up to five times to a constant 3H/14C ratio. RESULTS: Testosterone was taken up by both cell types; significant amounts of 5 alpha-dihydrotestosterone were recovered inside beard cells, but not in scalp cells, whereas androstenedione was identified in both. An unidentified compound was present intracellularly in both cell types, but was not present in the culture medium. 5 alpha-Dihydrotestosterone was present only in the culture medium of beard cells but androstenedione was present in a similar amount in the medium from both cell types. The presence of other steroids could not be confirmed in either the cell extracts or the culture medium. CONCLUSIONS: The production of 5 alpha-dihydrotestosterone by beard cells concurs with the poor beard growth in men with 5 alpha-reductase deficiency, supporting our hypothesis that androgens mediate their effects on the hair follicle via the mesenchyme-derived dermal papilla.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Mechanism of androgen action in cultured dermal papilla cells derived from human hair follicles with varying responses to androgens in vivo.

Androgens are major regulators of human hair growth, but their effects vary: many follicles are stimulated by androgens, e.g., beard; some remain unaffected, e.g., eyelashes; whereas scalp follicles undergo regression and balding in genetically disposed individuals. Because the dermal papilla controls many aspects of the hair follicle, androgens may act via the dermal papilla, affecting the other follicular components indirectly. In this hypothesis androgens would alter dermal papilla cell production of regulatory substances, e.g., growth factors and/or extracellular matrix components. To test this theory the mechanism of androgen action has been compared in primary lines of dermal papilla cells cultured from androgen-dependent follicles and relatively androgen-independent non-balding scalp. Androgen receptor levels were assayed by saturation analysis (9-10 points; 0.05-10 nmol/l) using the synthetic androgen [3H]-mibolerone and specificity was confirmed by competition studies. Androgen metabolism was investigated both intracellularly and in the media after a 2-h incubation with 5 nM [3H]-testosterone. Carrier and [14C] steroids were added to the extracts before separation by thin-layer chromatography; steroid identity was confirmed by recrystallization. Dermal papilla cells from androgen-dependent follicles contained higher levels of specific, high-affinity, low-capacity androgen receptors than non-balding scalp cells. Testosterone metabolism also varied with beard, public and scalp cells containing testosterone and androstenedione intracellularly, but only beard cells producing 5 alpha-dihydrotestosterone, in line with the scanty beard growth found in 5 alpha-reductase deficiency. Elsewhere we have shown that cultured dermal papilla cells produce extracellular matrix components and mitogenic factors. These results all concur with our original hypothesis and suggest that further studies of such cells may elucidate the paradoxical effects of androgens on human hair follicles.

Androgens↗
PubMed1992

Glycosaminoglycan synthesis by cultured human hair follicle dermal papilla cells: comparison with non-follicular dermal fibroblasts.

The extracellular matrix of the hair follicle dermal papilla is rich in glycosaminoglycans, the expression of which varies during the hair growth cycle being maximal in anagen and becoming undetectable as the follicle enters telogen. These observations, together with other experimental and clinical evidence, suggest that glycosaminoglycans may be involved in regulating hair growth. To investigate the metabolism of glycosaminoglycans by the dermal papilla we have measured the incorporation of radiolabelled precursors into glycosaminoglycans released into extracellular matrix and culture medium by cultured human dermal papilla cells. We also studied glycosaminoglycan synthesis by cells cultured from the lower follicular connective tissue sheath and by non-follicular dermal fibroblasts. Compared with dermal fibroblasts, dermal papilla cells showed a three to fourfold higher level of incorporation of 35S-sulphate and 3H-glucosamine into extracellular matrix glycosaminoglycans. Dermal papilla cells also released more 3H-glucosamine-labelled glycosaminoglycan into culture medium than dermal fibroblasts but there was no difference in 35S-sulphate labelling. These findings indicate that dermal papilla cells maintain a high level of glycosaminoglycan synthesis in vitro. Specific enzyme/chemical degradation showed that dermal papilla cells and dermal fibroblasts synthesized the same glycosaminoglycan types. However, the results suggested that dermal papilla glycosaminoglycans are less sulphated than those synthesized by dermal fibroblasts and that a higher proportion of sulphated glycosaminoglycans is retained in an extracellular matrix. The synthesis of glycosaminoglycans by connective tissue sheath cells was similar to that of dermal papilla cells, supporting the view that the dermal papilla and connective tissue sheath share certain properties.

Cells, Cultured↗
PubMed1992

Cultured dermal papilla cells from androgen-dependent human hair follicles (e.g. beard) contain more androgen receptors than those from non-balding areas of scalp.

Androgens stimulate hair growth in many areas, e.g. the beard; they also induce regression and balding on the scalp with increasing age in genetically disposed individuals. The cause(s) of this biological conundrum is unknown but age-related; androgen-potentiated changes also occur in the prostate. The mesenchyme-derived dermal papilla situated at the base of the hair follicle is thought to play an important role in regulating the growth and development of the follicular epithelium. Since androgens probably act on the hair follicle via the dermal papilla, cultures of dermal papilla cells from human hair follicles with differing responses to androgens in vivo have been established and their ability to bind androgens assessed. Receptor binding was assayed by saturation analysis (0.05-10 nmol/l) using the synthetic non-metabolizable androgen, [3H]mibolerone. Shionogi 115 cells were also assayed as a positive control. Specific high-affinity low-capacity androgen receptors were identified in 12 dermal papilla primary cell lines with similar characteristics to established androgen receptors. Cells from androgen-sensitive follicles (beard, scrotum and pubis) contained higher levels of androgen receptors than those derived from relatively androgen-insensitive non-balding scalp follicles whether the receptor content was calculated in relation to cell number, protein or DNA content of the cells. These results support the hypothesis that androgens act on hair follicles via the dermal papilla in vivo and demonstrate that dermal papilla cells exhibit an altered phenotype in culture which depends on the body site from which they were derived.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗