BRIDGING THE “DEAD HAIR”—“LIVE FOLLICLE” 317 exposed edge, cells in the cortex become elongated and the hair keratins are organized into macrofi brils (15,25,26). These are complex structures containing intermediate fi la- ments embedded in a matrix composed of keratin-associated proteins (KAPs). The inter- mediate fi laments are collections of heterodimers of hair keratin proteins. Macrofi bril structures are stabilized by cross-links established by a range of disulphide bonds, ionic bonds and hydrogen bonds (25–27). The array of hair keratins and KAPs expressed in the HS and other HF compartments have been very well characterized (14,22,23,28– 30). Although these clearly determine the structure and strength of the HS, researchers have failed to understand how the modulation of HM keratinocyte activities correlates with hair keratins and KAP’s expression and infl uences HS properties. Some attempts have been made by “live follicle” researchers, who have shown that precortical hair kera- tins can be regulated by selected endogenous and exogenous factors ex vivo, using human HF organ culture (31,32). Unfortunately, methodological limitations prevented these researchers from translating their fi ndings to changes in HS quality. In addition, de- creased expression of selected hair keratins and KAPs is correlated with hair ageing (33), which is also characterized by thinning of the HS (34). Ultimately, the changes occurring in the “live follicle” contribute to alterations in char- acter of “dead hair” structure and quality however, research within the two HF worlds remains separated. This is quite surprising considering that these two worlds share the hair care market and try to satisfy common consumers. The “live follicle” and “dead hair” researchers have clearly different scientifi c interests and different backgrounds biologists are unraveling the secret life of the “live follicle,” whereas physicists and chemists are involved in learning about the material properties of the “dead hair.” Indeed, an intense literature search is required to reveal the aspects of the “live follicle” that affect the “dead hair” structure and quality. Most of such studies come from the wool industry, for which obviously wool hair fi ber quality is more important than hair fi ber length and, therefore, anagen maintenance. For example, an elegant study by Bond et al. (35,36) showed that ex vivo treatment of wool adult anagen HFs with fi broblast growth factors 1 and 2, whose receptors are expressed in the living HFs, has an impact on protein synthesis for the “dead hair” but did not alter the cells of the “live” HM. Although the authors have not analyzed the hair fi ber quality, they suggested that these changes likely affect tensile strength. In humans, some information can be extrapolated from genetic hair conditions. It is clear that anything that interferes with the production of “dead hair” shaft keratins during keratinocyte differentiation in the “live follicle” results in decrease in HS thickness and integrity, as seen in monilethrix (5,23,37). Regulation of the production of trichohyalin (THH) or its solubility contributes to HS abnormalities. Also, genetic mutations of genes encoding for THH or enzymes involved in THH post-translational modifi cation result in the condition called uncombable hair syndrome, manifested by a production of silvery- blond or yellowish-colored disorderly hairs, which are diffi cult to comb (38). Hair disor- ders characterized by abnormal HS curvature have been linked to changes in the expression of IRS keratins (3,5). Patients with defi ciency in Adenosine triphosphate (ATP)7A (or Menkes’ ATPase), which is involved in copper traffi cking, feature hypopigmented brittle hairs, also called kinky hairs (39,40). Mutation in genes encoding for a protein involved in the cell cycle, namely, M phase–specifi c Serine/threonine-protein kinase (PLK1), causes trichothiodystrophy, a syndrome in which hairs are brittle because of defi ciency in sulfur, a fundamental component for intermediate fi lament cross-linking in the HS (41). We have
JOURNAL OF COSMETIC SCIENCE 318 recently demonstrated that patients showing a new form of ectodermal dysplasia carry the mutation in gene TSPEAR encoding the thrombospondin-type laminin G domain and EAR repeats protein. This mutation causes scalp hypotrichosis as a result of reduced number of HFs and abnormalities in HS cuticle cells, which appeared fl attened. Interestingly, the silencing of TSPEAR in mouse HFs ex vivo promoted HM keratinocyte apoptosis and reduction in the hair bulb diameter (42). TSPEAR defi ciency negatively impacts HF structure and HS quality by regulating the expression of Notch homolog 1, translocation- associated (Drosophila) (NOTCH)1 (42), a protein involved in HF development and regeneration (6,43). Among “live follicle” researchers, it is very well known that insulin-like growth factor (IGF)-1 signaling is fundamental for hair cycle regulation and anagen maintenance (44– 46). Dysregulation of the insulin pathway in the dermal papilla fi broblasts is associated with androgenetic alopecia (47), and the addition of insulin or IGF-1 to the culture me- dium is essential for delaying catagen during HF organ culture ex vivo (48–50). Surpris- ingly, only few studies reported about the role of the IGF-1 pathway on HS quality and structure. DNA polymorphism of IGF-binding protein (IGFBP)-3 causes changes in combed cashmere weight, cashmere fi ber length, and guard hair length but not in cash- mere fi ber diameter (51). Interestingly, IGFBP5 is expressed in the HM, dermal papilla, and/or medulla in mice. However, only zigzag but not guard or awl HFs express IGFBP-5. Overexpression of IGFBP5 in vivo in the IRS and HS medulla results in hair bending and a thicker and longer HS (52). The fact that IGF-1 signaling is involved in hair bending was also confi rmed in human HF ex vivo (53). Overexpression of IGF-1 in the IRS and medulla in mice prevented hair bending in zigzag HFs but promoted the development of longer and thicker hair (44). Therefore, it is conceivable that any compounds increasing the expression of IGF-1 in human HFs would not only stimulate anagen prolongation but also could lead to the production of thicker, straighter HS. The Wingless/Integrated (WNT)/β-catenin, Sonic Hedgehog Homolog (SHH), trans- forming growth factor (TGF)β, and Bone Morphogenetic Protein (BMP) signaling path- ways are required for hair development and regeneration (1,6). In addition, the regulation of proteins belonging to WNT or BMP families is also implicated in HS quality and structure. Transgenic mice overexpressing BMP antagonist noggin in the ORS (K5 pro- moter) show bigger HFs and the replacement of zig-zag and auchene hairs by awl-like hairs with increased diameter (54). Interestingly, this effect is related to decrease in the expres- sion of Cdk inhibitor p27 (Kip1) and increased expression of selected cyclins (13) in the HM (54). Instead, overexpression of Wnt3 in the ORS (K14 promoter) causes the produc- tion of shorter and thinner hairs in mice (55). Similar phenotype was seen when the Wnt pathway was inhibited by overexpression of miR-214 in mouse keratinocytes (56). Also, the overexpression of only one selected growth factor in the HF ORS in vivo, such as vas- cular endothelial growth factor (VEGF), stimulates the production of thicker hairs, which is associated with the increase in hair bulb size and vascularization around HFs (57). Therefore, although it is evident that modulations in “live follicle” activities may highly contribute to HS quality, somehow, this aspect of HF research is often forgotten or lim- ited to gross information such as hair diameter. Very interesting conclusions can be drawn about the link between “live follicle” and “dead hair” based on the information extracted from several articles about the hair bene- fi ts of caffeine, the most widely used nutraceuticals used in cosmetic formulations. “Live follicle” researchers have known for some time that caffeine treatment of human HFs
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