As one of the main appendages of skin, hair follicles play an important role in the process of skin regeneration. Hair follicle is a tiny organ formed by the interaction between epidermis and dermis, which has complex and fine structure and periodic growth characteristics. The hair growth cycle is divided into three continuous stages, growth (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). And The Morphogenesis and cycle of hair follicles are regulated by a variety of signal pathways. When the signal molecules in the pathways are abnormal, it will affect the development and cycle of hair follicles, which will lead to hair follicle-related diseases.This article will review the structure, development, cycle and molecular regulation of hair follicles, in order to provide new ideas for solving diseases and forming functional hair follicle.

Morphogenesis, Growth Cycle and Molecular Regulation of Hair Follicles

The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin‐lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentation and its impact on melanocyte physiology remain unclear. Synthesizing our limited current understanding of this role, we specifically examine its impact on melanogenesis, oxidative biology, mitochondrial function, melanocyte senescence, and pigmentation‐related clock gene activity, with emphasis on human skin, yet without ignoring instructive pointers from nonhuman species. Given the strict dependence of melanocyte functions on the epithelial microenvironment, we underscore that melanocyte responses to melatonin are best interrogated in a physiological tissue context. Current evidence suggests that melatonin and some of its metabolites inhibit both, melanogenesis (via reducing tyrosinase activity) and melanocyte proliferation by stimulating melatonin membrane receptors (MT1, MT2). We discuss whether putative melanogenesis‐inhibitory effects of melatonin may occur via activation of Nrf2‐mediated PI3K/AKT signaling, estrogen receptor‐mediated and/or melanocortin‐1 receptor‐ and cAMP‐dependent signaling, and/or via melatonin‐regulated changes in peripheral clock genes that regulate human melanogenesis, namely Bmal1 and Per1. Melatonin and its metabolites also accumulate in melanocytes where they exert net cyto‐ and senescence‐protective as well as antioxidative effects by operating as free radical scavengers, stimulating the synthesis and activity of ROS scavenging enzymes and other antioxidants, promoting DNA repair, and enhancing mitochondrial function. We argue that it is clinically and biologically important to definitively clarify whether melanocyte cell culture‐based observations translate into melatonin‐induced pigmentary changes in a physiological tissue context, that is, in human epidermis and hair follicles ex vivo, and are confirmed by clinical trial results. After defining major open questions in this field, we close by suggesting how to begin answering them in clinically relevant, currently available preclinical in situ research models.

Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective

Cashmere goat from Inner Mongolia is an excellent local breed in China, and the related cashmere product is a kind of precious textile raw material with high price. Cashmere is generated from secondary hair follicles, which has obvious annual periodicity and includes three different stages: anagen, catagen, and telogen. Therefore, we investigated skin transcriptome data for 12 months using weighted gene co-expression network analysis (WGCNA) to explore essential modules, pathways, and genes responsible for the periodic growth and development of secondary hair follicles. A total of 17 co-expression modules were discovered by WGCNA, and there is a strong correlation between steelblue module and month (0.65, p = 3E-09), anagen (0.52, p = 1E-05), telogen (-0.6, p = 8E-08). Gene expression was generally high during late anagen to catagen (June to December), while expression was downregulated from telogen to early anagen (January-May), which is similar to the growth rule of hair follicle cycle. KEGG pathway enrichment analyses of the genes of steelblue module indicated that genes are mainly enriched in Cell cycle, Wnt signaling pathway, p53 signaling pathway and other important signal pathways. These genes were also significantly enriched in GO functional annotation of the cell cycle, microtubule movement, microtubule binding, tubulin binding, and so on. Ten genes (WIF1, WNT11, BAMBI, FZD10, NKD1, LEF1, CCND3, E2F3, CDC6, and CDC25A) were selected from these modules, and further identified as candidate biomarkers to regulate periodic development of hair follicles using qRT-PCR. The Wnt signaling pathway and Cell cycle play an important role in the periodic development of hair follicles. Ten genes were identified as essential functional molecules related to periodic development of hair follicle. These findings laid a foundation for understanding molecular mechanisms in biological functions such as hair follicle development and hair growth in cashmere goats. 

/pdf/identification-of-genes-related-to-hair-follicle-cycle-14cwbmsr.pdf

Identification of Genes Related to Hair Follicle Cycle Development in Inner Mongolia Cashmere Goat by WGCNA

Background Melatonin, a neurohormone, maybe involved in physiological processes, such as antioxidation, anti-inflammation, and hair growth. In the present study, we investigated the effects of melatonin on proliferation and intracellular signaling in DP cells using a three-dimensional (3D) spheroid culture system that mimics the in vivo hair follicle system. Methods DP cells were incubated in monolayer (2D) and 3D spheroid culture systems. The expression levels of melatonin receptors in DP cells were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. The effect of melatonin on the hair-inductive property of DP cells was analyzed using a WST-1-based proliferation assay, determination of DP spheroid size, expression analysis of DP signature genes, and determination of β-catenin stabilization in DP cells. The AKT/GSK3β/β-catenin signaling pathway associated with melatonin-induced β-catenin stabilization in DP cells was investigated by analyzing changes in upstream regulator proteins, including AKT, GSK3β, and their phosphorylated forms. Results The expression levels of the melatonin receptors were higher in human DP cells than in human epidermal keratinocytes and human dermal fibroblast cells. Comparing the expression level according to the human DP cell culture condition, melatonin receptor expression was upregulated in the 3D culture system compared to the traditional two-dimensional monolayer culture system. Cell viability analysis showed that melatonin concentrations up to 1 mM did not affect cell viability. Moreover, melatonin increased the diameter of DP cell 3D spheroids in a dose-dependent manner. Immunoblotting and qRT-PCR analysis revealed that melatonin upregulated the expression of hair growth-related genes, including alkaline phosphatase, bone morphogenetic protein 2, versican, and wingless-int 5A, in a melatonin receptor-dependent manner. Cell fractionation analysis showed that melatonin increased the nuclear localization of β-catenin. This result correlated with the increased transcriptional activation of T-cell factor/lymphoid enhancer factor-responsive luciferase induced by melatonin treatment. Interestingly, melatonin induced the phosphorylation of protein kinase B/AKT at serine 473 residue and GSK-3β at serine 9 residue. To determine whether AKT phosphorylation at serine 473 induced β-catenin nuclear translocation through GSK3β phosphorylation at serine 9, the PI3K/AKT inhibitor LY294002 was cotreated with melatonin. Immunoblotting showed that LY294002 inhibited melatonin-induced phosphorylation of GSK3β at serine 9 residue and β-catenin activation. Conclusion Collectively, this report suggests that melatonin promotes growth properties by activating the AKT/GSK3β/β-catenin signaling pathway through melatonin receptors.

Melatonin increases growth properties in human dermal papilla spheroids by activating AKT/GSK3β/β-Catenin signaling pathway

The growth of secondary hair follicles in cashmere goats follows a seasonal cycle. Melatonin can regulate the cycle of cashmere growth. In this study, melatonin was implanted into live cashmere goats. After skin samples were collected, transcriptome sequencing and histological section observation were performed, and weighted gene co-expression network analysis (WGCNA) was used to identify key genes and establish an interaction network. A total of 14 co-expression modules were defined by WGCNA, and combined with previous analysis results, it was found that the blue module was related to the cycle of cashmere growth after melatonin implantation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the first initiation of exogenous melatonin-mediated cashmere development was related mainly to the signaling pathway regulating stem cell pluripotency and to the Hippo, TGF-beta and MAPK signaling pathways. Via combined differential gene expression analyses, 6 hub genes were identified: PDGFRA, WNT5A, PPP2R1A, BMPR2, BMPR1A, and SMAD1. This study provides a foundation for further research on the mechanism by which melatonin regulates cashmere growth.

/pdf/identification-of-key-pathways-and-genes-that-regulate-26cdni88.pdf

Identification of key pathways and genes that regulate cashmere development in cashmere goats mediated by exogenous melatonin

Secondary hair follicle growth in cashmere goats has seasonal cycle changes, and melatonin (MT) has a regulatory effect on the cashmere growth cycle. In this study, the growth length of cashmere was measured by implanting MT in live cashmere goats. The results indicated that the continuous implantation of MT promoted cashmere to enter the anagen 2 months earlier and induce secondary hair follicle development. HE staining of skin tissues showed that the number of secondary hair follicles in the MT-implanted goats was significantly higher than that in the control goats (P < 0.05). Transcriptome sequencing of the skin tissue of cashmere goats was used to identify differentially expressed genes: 532 in February, 641 in October, and 305 in December. Fluorescence quantitative PCR and Western blotting results showed that MT had a significant effect on the expression of Wnt10b, β-catenin, and proteins in the skin tissue of Inner Mongolia cashmere goats. This finding suggested that MT alters the cycle of secondary hair follicle development by changing the expression of related genes. This research lays the foundation for further study on the mechanism by which MT regulates cashmere growth.

/pdf/melatonin-regulates-the-periodic-growth-of-cashmere-by-1xihsra9zn.pdf

Melatonin Regulates the Periodic Growth of Cashmere by Upregulating the Expression of Wnt10b and β-catenin in Inner Mongolia Cashmere Goats.

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Melatonin Regulates the Periodic Growth of Cashmere by Upregulating the Expression of Wnt10b and β-catenin in Inner Mongolia Cashmere Goats.