Copyright © 2003 European Molecular Biology Organization
Laminin-10 is crucial for hair morphogenesis
Jie Li,
et al

Discussion

This study, for the first time, describes the critical role of the extracellular matrix/BMZ in skin morphogenesis. We have shown that laminin-10 is the primary laminin of elongating hair germs, and that absence of laminin-10 results in arrest of hair follicle development at the hair germ elongation phase. Interestingly, the application of exogenous laminin-10 promoted restoration of hair follicle development in Lama5 –/– skin. To our knowledge, this is the first instance of protein-mediated therapy in the correction of a cutaneous developmental defect. The method we employed, incubation of full-thickness embryonic skin in a laminin-10-containing solution, effectively resulted in the diffusion of laminin-10 into the BMZ of developing hair follicles. ....snip.. .As small amounts of laminin-11 were present in our purified laminin-10 samples, we cannot rule out the possibility that laminin-11 might also facilitate hair follicle development. However, as laminin â2-deficient mice have no hair defects (Noakes et al., 1995), and a downregulation of the laminin â2 chain was seen during mouse hair germ elongation in our studies, it is not likely that laminin-11 plays a major role in hair follicle development in the skin.Our results, as well as the results of a number previous studies, suggest that laminin-10 supports hair follicle development through a mechanism other than the maintenance of dermal–epithelial cohesion. A comparison between inhibition of laminin-5 and laminin-10 in the skin illustrates this point. In human skin xenografts, laminin-5 antibodies induced extensive epidermal detachment (Lazarova et al., 2000; M.P.Marinkovich, unpublished data) within 24 h of application, while in our studies, skin treated with laminin-10 antibodies did not show blisters or epidermal detachment even after 3 weeks. Similarly, extensive blistering is seen in patients with HJEB, who lack laminin-5. Absence of laminin-5 in Lama3 –/– mice produced extensive epidermal detachment as well as detachment-associated cell death (anoikis) (Ryan et al., 1999). In contrast, in our studies, we were unable to demonstrate significant epidermal detachment or anoikis in Lama5 –/– mouse skin. On the other hand, while inhibition of laminin-10 in both human and murine skin produced marked effects on hair follicle development, no hair follicle defects were demonstrated in laminin-5/6 null mouse skin (Ryan et al., 1999), and hair follicle development is typically normal in HJEB patients (Skoven and Drzewiecki, 1979). In conclusion, laminin-5 and laminin-10 appear to have non-overlapping functions in the skin, with laminin-5 promoting epidermal adhesion and laminin-10 promoting epithelial development.In our studies of BMZ structure in Lama5 –/– skin, lamina densa assembly was markedly abnormal, while exogenous laminin-10 corrected these defects. These results highlight the role that laminin-10 plays in lamina densa assembly in epithelial BMZs. However, the question arises as to whether BMZ assembly is necessary for hair follicle formation. For example, a number of alterations of BMZ assembly have been described in skin that do not affect hair follicle development. The absence of â4 integrin in humans produces junctional epidermolysis bullosa with pyloric atresia. In this disease, hemidesmosome formation is markedly abnormal and dermal– epidermal cohesion is severely impaired, but hair follicle abnormalities have never been reported in conjunction with this syndrome (Fine et al., 2000). Similarly, â4 integrin null mice show a similar lack of epidermal cohesion and hemidesmosome formation, but normal hair follicle development. Even the combined absence of á6â4 integrin and á3 integrin in Intá3/Intá6 –/– mice, which produced extensive impairment of lamina densa and hemidesmosome formation as well as extensive disruption of epidermal adhesion, did not significantly affect hair follicle formation. From these observations, it appears likely that neither an epithelial attachment defect nor a BMZ assembly defect can by themselves account for the lack of hair follicle development in Lama5 –/– skin.In contrast to â4 or á3 integrin deficiency, ablation of â1 integrin markedly inhibited hair follicle development. Findings in â1 integrin conditionally null skin were remarkably similar to our findings with Lama5 –/– skin, and include formation of an interrupted lamina densa and arrest of hair follicle development at the hair germ elongation stage. These previous findings correlate well with our studies of antibody-induced â1 integrin inhibition in the developing human scalp xenografts, in which â1 inhibition inhibited hair follicle development. As á3â1 integrin is a major laminin-10 receptor (Kikkawa et al., 2000), these results support a model in which laminin-10 promotes hair follicle development through â1 integrin signaling. This remains to be further studied.It appears likely that the lack of epithelial proliferative downgrowths in mutant skin grafts are the direct result of impaired Shh production and signaling evidenced by a decrease in expression of Shh and its downstream effector Gli1 in Lama5 –/– skin. Thus, it is possible that interruption of a specific signaling pathway arrested hair follicle development in Lama5 –/– mice. Shh expression and signaling are known to depend on the correct signaling of regulators such as isoforms of the BMP, WNT and TGF families of proteins, and it is possible that laminin-10 may in turn influence the localization, expression or activity of one or more of these proteins. Of note, it is interesting that the alterations of epithelial development in Lama5 –/– skin are selective, and do not affect other aspects of skin development such as epidermal differentiation or blood vessel formation.As the effects of laminin-10 appear specifically directed at the elongating hair germ, it is tempting to speculate that laminin-10 required for this process would be located in the follicular epithelial BMZ and be of keratinocyte origin. Alternatively, it has previously been suggested that a dermal signal is required for elongation of hair germs. In particular, laminin-10 is a component of dermal blood vessels, and has been shown to act as a potent substrate for â1 integrin-mediated endothelial cell signaling and migration (Doi et al., 2002). Thus, it is possible that interactions mediated by laminin-10 in blood vessels could account for dermal contributions necessary for hair germ elongation. Additional experiments are currently under way to compare the contributions of keratinocyte and blood vessel laminin-10 towards hair follicle development.It is also possible that lack of laminin-10 could impair blood vessel function. This could produce hypoxic conditions which impact on hair follicle development either in the hair regrowth cycle or embryonic skin morphogenesis. However, blood vessels were shown to form in mutant skin, and viability in both Lama5 –/– and Lama5 +/+ grafts was equivalent, approaching 100%, and with a lack of significant apoptosis in the absence of laminin-10. Therefore, hypoxia as a sole explanation for lack of hair follicle development in Lama5 –/– grafts seems unlikely. Similarly, no differences in apoptosis were seen in â1 integrin-deficient hair follicles.

Edited for hair loss treatment blog

Normalisation of hair follicle morphology iin alopecia areata mice after hair loss treatment with squaric acid dibutylester.
Gardner S, et al

Hair loss in Alopecia areata is a non-scarring, reversible disorder, presumably caused by an autoimmune attack on anagen hair follicles. Treatments are numerous, and most of these are ineffective. However, the elicitation of contact dermatitis on the affected skin is commonly associated with hair regrowth. A major advance in the study of hair loss due to alopecia areata has been the introduction and characterisation of the C3H/HeJ mouse model that exhibits many features of the human disease. In this study we examined the effects of squaric acid dibutylester treatment on hair follicles and the associated leukocyte infiltrate in alopecia areata mice with hair lsss by light and transmission electron microscopic analysis. This was compared with unaffected normal mice and alopecic untreated mice. Experimental mice were treated unilaterally with the contact allergen squaric acid dibutylester and the skin was assessed after hair regrowth. The characteristic pathological picture of alopecia areata was observed in alopecic but not normal mice. Nine of eleven experimental mice regrew hair on the treated side only and this was associated with a reduction in peri/intrafollicular inflammatory cell infiltrates, hair follicle dystrophy, melanin incontinence/clumping, and an increase in the numbers of hair follicles in full anagen. This normalisation of hair follicle status after treatment reflects the successful reversal of disease in these mice. snip....

Does D matter? The role of vitamin D in hair disorders and hair follicle cycling.
Amor KT, Rashid RM, Mirmirani P.

Exerpt (edited for hair loss blog use)

...Another potential application for vitamin D is in hair loss due to scalp psoriasis, which is associated with an increased telogen to anagen ratio. Although vitamin D3 analogs have been used in combination or as an alternative to topical steroids to treat scalp psoriasis for many years, their ability to combat the associated alopecia has not been thoroughly evaluated. A placebo-controlled trial with 26 patients showed that calcipotriol did not affect the telogen to anagen ratio after 6 weeks of treatment [40], but the optimal effect of calcipotriol on scalp psoriasis is not seen until 8 weeks [41]. Thus, the follow up may have been too brief to detect an effect of calcipotriol on hair loss.

It has been suggested that an optimal concentration of vitamin D is necessary to delay the aging phenomena, including hair loss. A cross sectional study of 296 healthy men was done to determine the association, if any, between male pattern baldness and serum 25-hydroxyvitamin D levels [42]. Based on this study, the extent and severity of male pattern baldness does not appear to be associated with serum 25-hydroxyvitamin D levels (p=0.60) [42]. Additional studies in subjects with age-related or senescent thinning as well as in women with female pattern hair loss could be considered to see if there is an association of hair loss with serum 25-hydroxyvitamin D levels.

Because it is known that the absence of VDR leads to alopecia, it was hypothesized that there may be VDR gene polymorphisms (Bsml, Apal, and Taql) in patients with alopecia areata. A study of VDR genotypes in 32 patients with alopecia areata and 27 controls showed no association between these VDR gene polymorphisms and alopecia areata [43]. A separate study also showed that there was no relationship between the VDR gene FokI polymorphism and alopecia areata [44]. These studies were small and limited to only one ethnic group, Caucasians in Turkey.

Conclusion
Extensive data from animal models clearly show that the VDR, independent of vitamin D3 hormone, plays an important role in the hair follicle cycle, specifically anagen initiation. Studies have demonstrated the ability of vitamin D3 analogs to stimulate hair regrowth, but clinical trials of calcitriol in humans have been unable to replicate these results. Reasons for this may be that more potent analogs of vitamin D3 were used in the animal studies than the human trials. Also, the mechanism of hair recovery in nude mice may not be applicable to humans with alopecia. The latter is reflected in one study that used nude mice with congenital alopecia, which does not have an equivalent in humans. This review shows the need for further exploration of the role of vitamin D and the VDR in the hair cycle. For clinical hair disorders in which there is an abnormal hair cycle, such as chemotherapy-induced alopecia, treatments that up regulate the expression of the vitamin D receptor may be successful. Developments of such treatments are a future area of study. Furthermore, studies on the optimal levels of local and systemic vitamin D levels are still limited and there is currently no evidence-based data to recommend vitamin D supplementation for various types of alopecia. In order to fully understand the effects of vitamin D supplementation in hai rloss treatment, future studies should compare results in vitamin D deficient patients to those in vitamin D sufficient patients.

Hai rloss treatment

The importance of histopathologic aspects in of dissecting cellulitis of the scalp.
Brãniºteanu DE,.

hair loss blog edited

Dissecting cellulitis of the scalp or dissecting folliculitis also known as "perifoliculitis capitis abscedens et suffodiens" (PCAS), is a rare, severe and distinct dermatological disease and cause of hair loss. It most probably occurs because of follicular occlusion via hyperkeratosis, having the same mechanism of acnea conglobata and hidradenitis suppurativa. These dermatoses may be associated or may have an isolated evolution. PCAS is one of the primitive cicatricial air loss of neutrophilic type. What is characteristic for the histopathologic picture of the disease is the deep inflammatory infiltrate, placed at the reticular derm or hypoderm level. snip.. Here is the case of a 24-year-old male with records of acne conglobata and cicatricial hair loss of the scalp, with relapsed inflammatory nodular lesions on the surface of the alopecic plaques and follicular pustules on their margin. The patient had followed before hospitalizing a systemic treatment with antibiotics (azithromycin, tetracycline, ciprofloxacin, in therapeutic schemes that the patient cannot mention, but anyway of short time) and after that a treatment with retinoids (isotretinoin, 20-30 mg/day, in two successive therapies of one month each). The evolution of the disease under these treatments was with outbreaks and short times of remission of the acne lesions and nodular lesions of the scalp. The clinical diagnosis of PCAS is difficult, especially in the initial stage of the disease, as it was the case of the patient presented here. snip....

edited for hair loss blog use

Hair loss and hair loss treatment

Significance of hair root status method

Braun-Falco O, Heilgemeir GP

The significance of proposition of the hair root status method is reported. The percentage composition of the hair root patterns of neighboring areas of the capillitium and the behavior of the percentage of the individual hair root shapes were examined at time zero and 120 days later. These examinations were carried out in the frontal, parietal and occipital regions of each of 10 male test persons with clinically normal hair growth and statistically evaluated. The hair root pattern of neighboring areas is the same within the different regions of the capillitium. Thus the hair root patterns investigated in the different regions of the capillitium are representative of this respective region. The hair root patterns of males with clinically normal hair regrowth (for the frontal, parietal and occipital region) does not differ with time. Therefore, examination of the hair root pattern at four week intervals can be used for controlling the hair regrowth capacity and therapeutic effects. The significance of the hair root status method in treatment may be relative small in the individual case in a person with normal hair regrowth, but useful when evaluated in a collective of subjects.

Modified for hair regrowth blog

....better understanding of the EGF family ligands and receptors, as well as their interplay and physiological phases, has the potential to produce a revolution in the treatment of hair loss. Availability of topical EGFR blockers and the development of more specific molecules that will stimulate the hair regrowth pathways will build on the fact that EGFR blockade can produce long-term hair growth. An apparent lack of tolerance to the hair regrowth effect after long term treatment, as recently seen, contrasts with other systemic and cutaneous toxicities of medications from the EGFR blocking class, thus creating the possibility of clinically relevant long-lasting effects.

Edited for hair loss blog use