Hair Loss Treatment

EMBO J. 2003 May 15; 22(10): 2400–2410.

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skin xenografts, laminin-5 antibodies induced extensive epidermal detachment (Lazarova et al., 2000; M.P.Marinkovich, unpublished data) within 24 h of application, while in our studies, skin treated with laminin-10 antibodies did not show blisters or epidermal detachment even after 3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