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Elucidation of Hair Growth and Hair Pigmentation Promotion Effect of 3,4,5-Tri-O-Caffeoylquinic Acid

メリエム, ベジャウィ Meriem, Bejaoui 筑波大学

2020.07.27

概要

Hair follicle (HF) undergoes a regular cycle composed of three phases: anagen, catagen, and telogen. During anagen phase or the growth phase, dermal papilla cells (DPs) located at the proximal end of the HF, regulates the induction of the hair cycle and the formation of the hair shaft. Moreover, during this phase, the bulbar melanocytes are active and produce the pigment melanin. The HF enters then a regression phase (catagen) followed by a resting phase (telogen) where the hairs are normally shed. Various signaling pathways regulate the hair growth cycle, such as the canonical Wnt/β-catenin signaling as it is involved in the regulation of the development, growth, and proliferation of the HF and the regulation of the melanocytes and the pigmentation. Wnt/β- catenin activation in the HF initiates the anagen phase initiation by inducing the proliferation and differentiation of matrix cells producing the pigmented hair shaft. An alteration in the pathways regulating the HF, can lead to a shorten length of anagen phase and an increase rate of hair loss (alopecia) and hair graying (canities).

　As hair plays an important role in individual's general appearance, hair problems are a major concern in the modern society. Hair loss and hair graying are common disorders that appear both in men and women undependably of the age or the origin, yet the mechanism by which they occur is not well understood. The current available therapies rely on synthetic chemicals ingredients and have showed many severe side effects and temporary results. The Food and Drug Administration (FDA) have approved two treatment against hair loss: Minoxidil and Finasteride but unwanted sides effect were observed including: impotence, dizziness, unwanted grown hair, weakness, headache, skin rash, and others. Developing a safe drug with a lasting effect has become a necessity to treat hair disorders and to have an alternative therapy for promoting hair growth and pigmentation.

　In this context, caffeoylquinic acid (CQA) is a phenylpropanoid compound exhibiting several beneficial properties including anti-oxidant, anti-allergic, neuroprotective, and melanogenesis-regulating effects. TCQA or 3,4,5-tri-O-caffeoylquinic acid is a derivative of CQA and chlorogenic acid (CGA) family that has a stable albumin affinity and is composed of multi- esters formed between quinic acid and one-to-four residues of trans-caffeic acids. TCQA has been found to induce a powerful inhibitory activities against aldose reductase, hypertension, hyperglycemia, and Alzheimer's disease without unwanted secondary effects. Moreover, TCQA induces neurogenesis, improves learning and memory in aged mice, and promotes the differentiation of human neural stem cells, however its effect on hair growth and hair pigmentation promotion has not yet been assessed. In the present study, the effect of TCQA on the induction of hair pigmentation and growth through exploring the possible common pathways such as Wnt/β- catenin was investigated In this purpose, the dorsal back of eight-weeks-old C3H male mice was shaved and TCQA was applied topically for a month. Results showed that TCQA stimulated the induction and the acceleration of the anagen phase of the hair growth cycle compared to the untreated mice. TCQA significantly enhanced the hair growth by approximately 120% by the end of treatment. In contrast, for the control group, only 37% hair regrowth area was observed. In addition, the hair plucked from the treated area of TCQA-treated mice displayed a darker color compared with the control and melanin assay showed that the melanin content increased up to 175% after TCQA application. To uncover the mechanism behind the effect of TCQA on hair cycle, microarray analysis was conducted. An upregulation in hair growth- and pigmentation-associated genes was observed. Genes relevant in β-catenin binding, pigmentation, neural cells differentiation and migration, transcription regulation, and Wnt signaling were upregulated. On the other hand, genes involved in Wnt repression, melanin degradation, and β-catenin degradation complex were downregulated. Immunohistochemistry results from skin collected from the treated area, revealed an accumulation of β-catenin expression in the epidermis and the hair bulb where the DPs and the active melanocytes are located. These results demonstrated also an activation of Tyrosinase (TYR) involved in melanin synthesis, in the hair bulb, showing that the melanocyte are active and producing the pigment melanin. A staining of CD34 an anagen marker in the skin, showed the stimulation of this protein in TCQA-treated skin compared with the control. These immunohistochemistry results revealed that the HF from TCQA-treated mice are in the anagen phase of the hair cycle, which means that the hair matrix cells are differentiating to form the hair shaft and the melanocytes are active and produce the melanin.

　Furthermore, TCQA was used on human and mouse cell lines to further validate its effect on hair growth and melanogenesis. Human hair follicle dermal papilla cells (HFDPC) was cultured in the presence of the sample and the proliferation along with the ATP content were significantly enhanced upon the treatment. In addition, the protein and the gene expression of β-catenin was upregulated in TCQA-treated cells, even after inhibition with XAV939. This results prove further the effect of TCQA on the stimulation of hair growth via the activation of β-catenin in dermal papilla cells.

　Human melanocytes (HEM), melanin-producing cells and B16 murine melanoma cells (B16F10), were used to further validate the effect of TCQA on pigmentation. Melanin content along with the gene and protein expression of the melanogenesis enzymes TYR, TYRP1 (tyrosinase-related protein 1), and DCT (dopachrome tautomerase) were upregulated upon treatment. This effect is attributed to the activation of microphthalmia-associated transcription factor (MITF) the transcription factor of the melanogenesis enzymes caused by the enhancement of the expression of β-catenin known to activate Mitf.

　Taken together, the finding of this thesis showed that TCQA triggered the activation of Wnt/β-catenin pathway leading to the transition from telogen to anagen phase, anagen phase initiation and elongation, hair matrix differentiation, and hair shaft development and pigmentation.

　Furthermore, the observed stimulation of hair growth cycle was supported by the downregulation of telogen- and aging-associated genes, Wnt signal inhibitors, and melanin degradation-associated genes which contributed to further enhance the effect of β-catenin and Wnt proteins activation. TCQA successfully activated the proliferation of dermal papilla cells often considered the key regulator of hair growth cycle and the melanocytes, melanin-producing cells.

　In this context, the potential effect of TCQA on the activation of melanocytes through a communication with dermal papilla cells via Wnt/β-catenin will be looked at. Clinical studies would be however necessary to introduce TCQA as a safer drug to initiate the hair growth cycle and to enhance melanogenesis.

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