Follicular epithelia and dermal papillae of mouse vibrissal follicles qualitatively change their hair-forming ability during anagen

We studied the hair-forming ability of epithelium and the relevant activity of dermal papilla (DP) in mouse vibrissal follicles during the hair cycle. Follicles were transversely cut into four pieces and each of them was associated with an isolated DP and grafted beneath the kidney capsule to induce hair formation. Various hair-cycle combinations of the fragments and DPs were examined. Hairs were generated not only in the follicle fragment containing the bulge (fragment III) but also in the fragment between the bulge and hair bulb (fragment II). The hair-forming frequencies were affected by the hair cycle stages of both the follicle fragments and DPs. Fragment III at late anagen (LA) and fragment II at catagen frequently generated hairs when associated with early anagen (EA)-DPs, but infrequently with mid-anagen (MA)-DPs. Oppositely, anagen fragment II produced hairs at a high frequency with MA-DPs and at a low frequency with EA-DPs. Hair generation in anagen fragment II is an unexpected finding because previous studies suggested that, during anagen, this region does not contain clonogenic epithelial cells that have been believed to be crucial for hair formation. Therefore, non-clonogenic epithelial cells would be able to generate hairs as well as clonogenic ones, and they should have a latent hair-forming ability that could be more effectively awakened by MA-DP than by EA-DP stimuli. Non-clonogenic epithelial cells might be a dormant phase of hair precursor cells. Proliferating follicular epithelial cells were detected in the middle and lower outer root sheath throughout the hair cycle but scarcely at LA. These findings suggest that the hair inductivity of DPs should be altered between EA and MA, and follicular epithelial cells would change their DP stimuli-directed hair-forming ability around LA, probably linked to the proliferative activity.     

Melanocyte subpopulation turnover during the human hair cycle: an immunohistochemical study

The human hair cycle is characterized by successive phases of growth and involution that imply tissue regression and regeneration. As a consequence, the hair melanin unit has to be renewed in a cyclic manner. Actually, the behavior of human hair follicle melanocytes throughout the hair cycle has been poorly studied. Thus, the origin of melanocytes present in the bulb after human hair regeneration is still not clarified, and neither are the events that control the melanin biosynthesis activity in the human hair bulb. In this study, we showed at the cellular level that in human pigmented hair follicles, the expression of tyrosinase and tyrosinase-related protein-1 (TRP-1) was detectable during the anagen phases III/IV through VI, only in those melanocytes which were located in the bulb. During the catagen phase, the two evaluated melanogenic enzymes were detectable no more, although melanocytes were still present in the preceding bulbar area. The epithelial column of catagen follicles and the capsule of telogen follicles also contained inactive melanocytes as evidenced by pMel-17 labeling. At the induction of a new anagen hair follicle, some melanocytes were committed to cell division, but only when located in the nascent bulb close to the dermal papilla. Our results emphasize the close relationship between melanogenesis and the hair cycle and suggest that in humans, melanogenesis is restricted to anagen hair follicles not because of the regulation of tyrosinase activity, but because of melanogenic enzyme expression, e.g., tyrosinase and TRP-1. Furthermore, the fact that in the newly developing anagen hair follicles, cell-division commitment and tyrosinase and TRP-1 expression were observed in melanocytes only when located in the nascent bulb suggests a highly regio-specific melanocyte stimulation in early the anagen phase.     

IGF1和IGF1R在小鼠第一个毛囊生长周期皮肤的表达

毛囊生长周期中,真皮乳头和毛基质间的基质 上皮信号调控细胞的增殖和分化。多功能细胞调控因子胰岛素样生长因子1（IGF1)是该信号路径的成员之一。第1个毛囊生长周期决定着毛囊的正常生长和发育,但IGF1在此期的作用未见报道。实时荧光定量PCR结果显示,IGF1在生长期皮肤中的相对表达量最低,在退化期表达量最高,在静止期表达量又降低。与生长初期相比,IGF1在退化期和静止期的表达量呈差异极显著（P＜0.01）;胰岛素样生长因子1受体（IGF1R）在生长期皮肤中的相对表达量最高,在退化期表达量最低,而在静止期表达量又升高。与生长初期相比,IGF1R在退化期和静止期的表达量呈差异极显著（P＜0.01）。Western 印迹结果显示,IGF1和IGF1R蛋白在小鼠皮肤第1个毛囊生长周期各阶段的表达趋势分别与其mRNA的表达趋势一致;免疫组织化学结果表明,IGF1主要分布在小鼠表皮,而IGF1R免疫阳性在小鼠毛囊毛球部、内外根鞘和毛乳头均有分布。以上实验结果揭示,IGF1和IGF1R在小鼠皮肤第1个毛囊生长周期的各阶段的差异性表达,可能在毛囊生长周期各阶段的转化过程中参与了黑色素的形成。然而,IGF1和IGF1R表达趋势不一致,提示IGF1在小鼠皮肤中发挥作用时,并非只与IGF1R结合才能发挥作用。     

Expression of basement membrane components through morphological changes in the hair growth cycle

The amount and distribution of fibronectin associated with hair follicles was found to vary during the hair growth cycle in the rat. Immunocytochemical staining of follicles in mid-late anagen (the growth stage) revealed the presence of fibronectin in the dermal papilla matrix, in the basement membrane separating this from the epithelial cells of the hair bulb, and in the basement membrane and connective tissue sheath which underly the cells of the outer root sheath. Early in catagen, the transitional stage, staining of the dermal papilla matrix disappeared. Fibronectin persisted in the basement membrane and connective tissue sheath, which undergo corrugation and apparent thickening in catagen. After follicle shortening, the telogen (resting) stage is reached, at which point fibronectin staining was found to be minimal, being restricted to the basement membrane around the secondary germ. The onset of anagen, involving cell division and follicle elongation, was associated with a great increase in the amount of fibronectin in this zone and in and around the dermal papilla. Analysis of entry into anagen by [3H]thymidine incorporation and autoradiography revealed that growth could be detected before the increase in fibronectin expression. However, growing cells, even in a suprabasal position, always had some fibronectin at their surface. Immunoelectron microscopy of early anagen follicles confirmed the light microscopic findings and also showed that fibronectin was present in small vesicles close to the surface of dermal papilla and some epithelial cells. Increased deposition of laminin and type IV collagen in early anagen follicles was also noted, emphasizing the importance of basement membrane components during morphogenetic events in vivo.     

Expression of galectin-1 and -3 and of accessible binding sites during murine hair cycle

Although protein-carbohydrate interactions are supposed to play key roles in cell adhesion, signalling and growth control. Their exact role in skin physiology has only recently been investigated. The endogenous lectins galectin-1 and galectin-3 have been identified in skin including hair follicles. Here, we analyzed the expression and distribution of these galectins and their binding sites in C57BL/6 mice during hair cycle. The expression of galectin-1 and galectin-3 binding sites was found to be predominantly hair cycle-dependent showing some overlapping to the expression of galectin-1 and -3. The outer root sheath (ORS) expressed galectin-1 binding sites during anagen IV to VI and in early catagen, whereas galectin-1 was expressed from early anagen to late catagen. The ORS expressed galectin-3 binding sites during catagen transition corresponding to a galectin-3 expression during anagen V and catagen. The innermost layer of the ORS expressed galectin-3 binding sites during anagen VI until catagen VIII, but galectin-3 during anagen III to IV and catagen. The inner root sheath (IRS) expressed galectin-3 binding sites only in anagen IV but missed expression of any of the two galectins. The matrix cells expressed galectin-3 binding sites in catagen II-III as well as galectin-3 during anagen V to catagen IV. The present study provides the first evidence for a cycle-related expression of both galectin-1 and -3 and their binding sites during murine hair cycle.     

Estrogen leads to reversible hair cycle retardation through inducing premature catagen and maintaining telogen

Estrogen dysregulation causes hair disorder. Clinical observations have demonstrated that estrogen raises the telogen/anagen ratio and inhibits hair shaft elongation of female scalp hair follicles. In spite of these clinical insights, the properties of estrogen on hair follicles are poorly dissected. In the present study, we show that estrogen induced apoptosis of precortex cells and caused premature catagen by up-regulation of TGF β2. Immediately after the premature catagen, the expression of anagen chalone BMP4 increased. The up-regulation of BMP4 may further function to prevent anagen transition and maintain telogen. Interestingly, the hair follicle stem cell niche was not destructed during these drastic structural changes caused by estrogen. Additionally, dermal papilla cells, the estrogen target cells in hair follicles, kept their signature gene expressions as well as their hair inductive potential after estrogen treatment. Retention of the characteristics of both hair follicle stem cells and dermal papilla cells determined the reversibility of the hair cycle suppression. These results indicated that estrogen causes reversible hair cycle retardation by inducing premature catagen and maintaining telogen.     

Nerve growth factor and its precursor differentially regulate hair cycle progression in mice.

Nerve growth factor (NGF) promotes proliferation via its high affinity receptor (TrkA). Its precursor proNGF promotes apoptosis via the pan-neurotrophin-receptor p75. Recently, we have identified NGF and p75 as important hair growth terminators. However, if proNGF is involved or if NGF can also promote hair growth via TrkA is unclear. By RT-PCR we found that NGF/proNGF mRNA levels peak during early anagen in murine back skin, whereas NGF/proNGF protein levels peak during catagen, indicating high turnover in early anagen and protein accumulation in catagen. By immunohistochemistry, NGF and TrkA are found in the proliferating compartments of the epidermis and hair follicle throughout the cycle. In contrast, strong proNGF is found in the highly differentiated inner root sheath and adjacent to the p75+ regressing epithelial strand in catagen. Commercial 7S NGF, which contains both NGF and proNGF, promotes anagen development in organ-cultured early anagen mouse skin, whereas it promotes catagen development in late anagen skin. Together, our findings suggest an anagen-promoting or anagen-supporting role for NGF/TrkA, and a catagen-promoting role for proNGF/p75 interactions. This has important implications for the future design of specific neurotrophin receptor ligands as novel pharmaceuticals in the modification of tissue remodeling processes such as hair growth or wound healing.     

Wnt3a在毛囊及黑素细胞谱系中的表达

目的:探讨毛囊周期中,Wnt3a在毛囊及黑素细胞中的表达变化。方法:以DCT-LacZ转基因小鼠为动物模型,通过X-gal染色技术观察黑素细胞谱系在小鼠皮肤中的分布情况;采用X-gal染色结合免疫组化方法检测Wnt3a在毛囊及黑素细胞谱系中的表达情况;采用RT-PCR方法对小鼠皮肤全层Wnt3a和TYR的mRNA表达进行半定量分析。结果:在生长期毛囊中,Wnt3a蛋白在表皮、毛囊外根鞘Bulge区、内根鞘以及毛球部均有表达,在黑素干细胞与黑素细胞也观察到Wnt3a;在退化期,Wnt3a的表达逐渐减弱,仅在外根鞘有较弱的表达,但黑素干细胞中没有观察到Wnt3a;在静止期,几乎检测不到Wnt3a的表达;TYR mRNA与Wnt3a mRNA在毛囊周期中的表达模式一致,在生长期最强,退化期减弱,静止期最弱。结论:Wnt3a可能对黑素细胞谱系分化起到促进作用。     

Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen

The lowermost portion of the resting (telogen) follicle consists of the bulge and secondary hair germ. We previously showed that the progeny of stem cells in the bulge form the lower follicle and hair, but the relationship of the bulge cells with the secondary hair germ cells, which are also involved in the generation of the new hair at the onset of the hair growth cycle (anagen), remains unclear. Here we address whether secondary hair germ cells are derived directly from epithelial stem cells in the adjacent bulge or whether they arise from cells within the lower follicle that survive the degenerative phase of the hair cycle (catagen). We use 5-bromo-2'-deoxyuridine to label bulge cells at anagen onset, and demonstrate that the lowermost portion of the bulge collapses around the hair and forms the secondary hair germ during late catagen. During the first six days of anagen onset bulge cells proliferate and self-renew. Bulge cell proliferation at this time also generates cells that form the future secondary germ. As bulge cells form the secondary germ cells at the end of catagen, they lose expression of a biochemical marker, S100A6. Remarkably, however, following injury of bulge cells by hair depilation, progenitor cells in the secondary hair germ repopulate the bulge and re-express bulge cell markers. These findings support the notion that keratinocytes can "dedifferentiate" to a stem cell state in response to wounding, perhaps related to signals from the stem cell niche. Finally, we also present evidence that quiescent bulge cells undergo apoptosis during follicle remodeling in catagen, indicating that a subpopulation of bulge cells is not permanent.     

Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin

MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205.     

Involvement of hepatocyte growth factor/scatter factor and met receptor signaling in hair follicle morphogenesis and cycling.

HGF/SF and its receptor (Met) are principal mediators of mesenchymal-epithelial interactions in several different systems and have recently been implicated in the control of hair follicle (HF) growth. We have studied their expression patterns during HF morphogenesis and cycling in C57BL/6 mice, whereas functional hair growth effects of HGF/SF were assessed in vivo by analysis of transgenic mice and in skin organ culture. In normal mouse skin, follicular expression of HGF/SF and Met was strikingly localized: HGF/SF was found only in the HF mesenchyme (dermal papilla fibroblasts) and Met in the neighboring hair bulb keratinocytes. Both HGF/SF and Met expression peaked during the initial phases of HF morphogenesis, the stage of active hair growth (early and mid anagen), and during the apoptosis-driven HF regression (catagen). Met+ cells in the regressing epithelial strand appeared to be protected from undergoing apoptosis. Compared to wild-type controls, transgenic mice overexpressing HGF/SF under the control of the MT-1 promoter had twice as many developing HF and displayed accelerated HF development on postnatal day 3. They also showed significant catagen retardation on P17. In organ culture and in vivo, HGF/SF i.c. resulted in a significant catagen retardation. These results demonstrate an important role of HGF/SF and Met in murine hair growth control and suggest that Met-mediated signaling might be exploited for therapeutic manipulation of human hair growth disorders.-Lindner, G., Menrad, A., Gherardi, E., Merlino, G., Welker, P., Handjiski, B., Roloff, B., Paus, R. Involvement of hepatocyte growth factor/scatter factor and Met receptor signaling in hair follicle morphogenesis and cycling.     

Dermal papilla cells and melanocytes response to physiological oxygen levels depends on their interactions

BackgroundHuman dermal papilla (DP) cells and melanocytes (hMel) are central players in hair growth and pigmentation, respectively. In hair follicles (HFs), oxygen (O₂) levels average 5%, being coupled with the production of reactive oxygen species (ROS), necessary to promote hair growth.Materials and MethodsDP cell and hMel proliferation and phenotype were studied under physiological (5%O₂, physoxia) or atmospheric (21%O₂, normoxia) oxygen levels. hMel‐DP cells interactions were studied in indirect co‐culture or by directly co‐culturing hMel with DP spheroids, to test whether their interaction affected the response to physoxia.ResultsPhysoxia decreased DP cell senescence and improved their secretome and phenotype, as well as hMel proliferation, migration, and tyrosinase activity. In indirect co‐cultures, physoxia affected DP cells’ alkaline phosphatase (ALP) activity but their signalling did not influence hMel proliferation or tyrosinase activity. Additionally, ROS production was higher than in monocultures but a direct correlation between ROS generation and ALP activity in DP cells was not observed. In the 3D aggregates, where hMel are organized around the DP, both hMel tyrosinase and DP cells ALP activities, their main functional indicators, plus ROS production were higher in physoxia than normoxia.ConclusionsOverall, we showed that the response to physoxia differs according to hMel‐DP cells interactions and that the microenvironment recreated when in direct contact favours their functions, which can be relevant for hair regeneration purposes.     

Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo.

The regression phase of the hair cycle (catagen) is an apoptosis-driven process accompanied by terminal differentiation, proteolysis, and matrix remodeling. As an inhibitor of keratinocyte proliferation and inductor of keratinocyte apoptosis, transforming growth factor beta1 (TGF-beta1) has been proposed to play an important role in catagen regulation. This is suggested, for example, by maximal expression of TGF-beta1 and its receptors during late anagen and the onset of catagen of the hair cycle. We examined the potential involvement of TGF-beta1 in catagen control. We compared the first spontaneous entry of hair follicles into catagen between TGF-beta1 null mice and age-matched wild-type littermates, and assessed the effects of TGF-beta1 injection on murine anagen hair follicles in vivo. At day 18 p.p., hair follicles in TGF-beta1 -/- mice were still in early catagen, whereas hair follicles of +/+ littermates had already entered the subsequent resting phase (telogen). TGF-beta1-/- mice displayed more Ki-67-positive cells and fewer apoptotic cells than comparable catagen follicles from +/+ mice. In contrast, injection of TGF-beta1 into the back skin of mice induced premature catagen development. In addition, the number of proliferating follicle keratinocytes was reduced and the number of TUNEL + cells was increased in the TGF-beta1-treated mice compared to controls. Double visualization of TGF-beta type II receptor (TGFRII) and TUNEL reactivity revealed colocalization of apoptotic nuclei and TGFRII in catagen follicles. These data strongly support that TGF-beta1 ranks among the elusive endogenous regulators of catagen induction in vivo, possibly via the inhibition of keratinocyte proliferation and induction of apoptosis. Thus, TGF-betaRII agonists and antagonists may provide useful therapeutic tools for human hair growth disorders based on premature or retarded catagen development (effluvium, alopecia, hirsutism).     

常见毛囊细胞角蛋白在毛囊周期中的表达研究

目的探讨常见毛囊细胞角蛋白在毛囊周期中的表达特征。 方法取毛囊发育期、生长期启动、生长期、退化期和静止期的小鼠皮肤,石蜡切片后通过免疫荧光的方法,检测细胞角蛋白Krt5、Krt6、Krt10、Krt14、Krt15和Krt19的表达情况。 结果Krt5在静止期和生长期启动表达于所有毛囊上皮细胞,在其他时期表达不一致;Krt6表达于所有时期的外根鞘细胞和内根鞘细胞;Krt10表达于生长期和退化期的毛母质和内根鞘细胞,在其他时期表达不一致;Krt14在生长期和退化期表达于所有毛囊上皮细胞,在其他时期表达不一致;Krt15和Krt19表达于毛囊发育期、生长期启动和静止期的毛囊隆突区细胞,在生长期和退化期表达不一致。 结论角蛋白作为毛囊结构或毛囊干细胞标记物仅适用于特定的毛囊周期。研究者在使用毛囊角蛋白作为标记物时,应首先明确其在毛囊周期中的表达情况。     

Analysis of the expression pattern of involucrin in human scalp skin and hair follicles: hair cycle-associated alterations

Involucrin is a structural component of the keratinocyte cornified envelope that is expressed early in the keratinocyte differentiation process. It is a component of the initial envelope scaffolding and considered as a marker for keratinocyte terminal differentiation. The expression pattern of involucrin in human scalp skin and hair follicle cycle stages is not fully explored. This study addresses this issue and tests the hypothesis that "the expression of involucrin undergoes hair follicle cycle-dependent changes". A total of 50 normal human scalp skin biopsies were examined (healthy females, 51-62?years) using immunofluorescence staining methods and real-time PCR analysis. In each case, 50 hair follicles were analyzed (35, 10 and 5 follicles in anagen, catagen and telogen, respectively). Involucrin was prominently expressed in the human scalp skin and hair follicles, on both gene and protein levels. The protein expression showed hair follicle cycle-associated changes i.e. a very strong expression during early and mature anagen, intermediate to strong expression during catagen and prominent decline in the telogen phase. The expression value of involucrin in both anagen and catagen was statistically significantly higher than that of telogen hair follicles (p?相似文献   

Circadian Clock Genes Contribute to the Regulation of Hair Follicle Cycling

Hair follicles undergo recurrent cycling of controlled growth (anagen), regression (catagen), and relative quiescence (telogen) with a defined periodicity. Taking a genomics approach to study gene expression during synchronized mouse hair follicle cycling, we discovered that, in addition to circadian fluctuation, CLOCK–regulated genes are also modulated in phase with the hair growth cycle. During telogen and early anagen, circadian clock genes are prominently expressed in the secondary hair germ, which contains precursor cells for the growing follicle. Analysis of Clock and Bmal1 mutant mice reveals a delay in anagen progression, and the secondary hair germ cells show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting that circadian clock genes regulate anagen progression via their effect on the cell cycle. Consistent with a block at the G1 phase of the cell cycle, we show a significant upregulation of p21 in Bmal1 mutant skin. While circadian clock mechanisms have been implicated in a variety of diurnal biological processes, our findings indicate that circadian clock genes may be utilized to modulate the progression of non-diurnal cyclic processes.     

Skin aging: Dermal adipocytes metabolically reprogram dermal fibroblasts

Emerging data connects the aging process in dermal fibroblasts with metabolic reprogramming, provided by enhanced fatty acid oxidation and reduced glycolysis. This switch may be caused by a significant expansion of the dermal white adipose tissue (dWAT) layer in aged, hair-covered skin. Dermal adipocytes cycle through de-differentiation and re-differentiation. As a result, there is a strongly enhanced release of free fatty acids into the extracellular space during the de-differentiation of dermal adipocytes in the catagen phase of the hair follicle cycle. Both caveolin-1 and adiponectin are critical factors influencing these processes. Controlling the expression levels of these two factors also offers the ability to manipulate the metabolic preferences of the different cell types within the microenvironment of the skin, including dermal fibroblasts. Differential expression of adiponectin and caveolin-1 in the various cell types may also be responsible for the cellular metabolic heterogeneity within the cells of the skin.     

In search of the "hair cycle clock": a guided tour

The hair follicle, a unique characteristic of mammals, represents a stem cell-rich, prototypic neuroectodermal-mesodermal interaction system. This factory for pigmented epithelial fibers is unique in that it is the only organ in the mammalian body which, for its entire lifetime, undergoes cyclic transformations from stages of rapid growth (anagen) to apoptosis-driven regression (catagen) and back to anagen, via an interspersed period of relative quiescence (telogen). While it is undisputed that the biological "clock" that drives hair follicle cycling resides in the hair follicle itself, the molecular nature of the underlying oscillator system remains to be clarified. To meet this challenge is of profound general interest, since numerous key problems of modern biology can be studied exemplarily in this versatile model system. It is also clinically important, since the vast majority of patients with hair growth disorders suffers from an undesired alteration of hair follicle cycling. Here, we sketch basic background information and key concepts that one needs to keep in mind when exploring the enigmatic "hair cycle clock"(HCC), and summarize competing models of the HCC. We invite the reader on a very subjective guided tour, which focuses on our own trials, errors, and findings toward the distant goal of unravelling one of the most fascinating mysteries of biology: Why does the hair follicle cycle at all? How does it do it? What are the key players in the underlying molecular controls? Attempting to offer at least some meaningful answers, we share our prejudices and perspectives, and define crucial open questions.     

Cutaneous application of α-methylspermidine activates the growth of resting hair follicles in mice

Recent studies using transgenic animals have revealed a crucial role for polyamines in the development and the growth of skin and hair follicles. In mammals, the growth of hair is characterized by three main cyclic phases of transformation, including a rapid growth phase (anagen), an apoptosis-driven regression phase (catagen) and a relatively quiescent resting phase (telogen). The polyamine pool during the anagen phase is higher than in telogen and catagen phases. In this study, we used α-methylspermidine, a metabolically stable polyamine analog, to artificially elevate the polyamine pool during telogen. This manipulation was sufficient to induce hair growth in telogen phase mice after 2 weeks of daily topical application. The application site was characterized by typical features of anagen, such as pigmentation, growing hair follicles, proliferation of follicular keratinocytes and upregulation of β-catenin. The analog penetrated the protective epidermal layer of the skin and could be detected in dermis. The natural polyamines were partially replaced by the analog in the application site. However, the combined pool of natural spermidine and α-methylspermidine exceeded the physiological spermidine pool in telogen phase skin. These results highlight the role of polyamines in hair cycle regulation and show that it is possible to control the process of hair growth using physiologically stable polyamine analogs.     

Hair cycle dynamics: the case of the human hair follicle

The existence of a growth and regeneration cycle makes the hair follicle a true paradigm of tissue homeostasis. Analysis of about 9000 cycles led us to propose a stochastic model of human hair dynamics. The existence of hair cycles implies that stem cells must be cyclically activated and hair melanin unit has to be renewed. Using different markers, we were able to identify two distinct epithelial stem cell reservoirs, located in the upper and lower thirds of the anagen hair follicle outer root sheath. These two reservoirs fuse during the regression phase and individualize again in the new forming anagen hair follicle. Using a set of antibodies specific of melanocyte lineage and melanogenesis, pigmentation unit turnover was followed throughout the entire hair cycle. In the terminal anagen hair, active melanocytes were localized on top of the dermal papilla, while amelanotic melanocytes were identified in the upper third of the outer root sheath (ORS). Those amelanotic melanocytes located in upper ORS probably represented a melanocyte reservoir for successive hair generation, since at the induction of anagen phase, some melanocytes were committed to cell division and melanogenesis was turned on, but only in the nascent hair bulb, close to the dermal papilla.