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Cinnamic acid promotes elongation of hair peg-like sprouting in hair follicle organoids via oxytocin receptor activation – Scientific Reports

Cinnamomum cassia is a tropical aromatic evergreen tree belonging to the Camphoraceae family, which is commonly used in traditional Chinese medicine. Moreover, revered as a traditional spice, its utilization transcends borders. In addition, Cinnamomum cassia extract has a wide range of pharmacological effects, including antitumor16, anti-inflammatory17, analgesic18, anti-obesity19, cardiovascular protective20, neuroprotective21, and anti-tyrosinase activity22. A recent study demonstrated that the application of Cinnamomum cassia extract to the skin of mice resulted in the promotion of hair growth23. These findings suggest that cinnamic acid, a component of Cinnamomum cassia, exhibits a hair growth-promoting effect, which is believed to be mediated through the upregulation of OXTR expression. The identification of cinnamic acid as a specific component with hair growth-promoting properties holds great promise for enhancing the effectiveness of hair growth products. In addition, the new understanding of the mechanism of hair growth-promoting effects mediated by oxytocin signaling will provide new insights by hair care science and help accelerate the search for new drugs targeting OXTR in the field of drug discovery.

The increase in cinnamic acid concentration decreased cell viability, which likely attributed to its acidifying effect on the pH of the culture medium, since obvious alteration in the phenol red color was observed in the medium. Higher concentrations of cinnamic acid may provide further effects by neutralizing the pH of culture medium.

Cinnamic acid caused a 1.25-fold increase in the elongation of hair sprouting length compared to the non-addition control in the hair growth assay using hair follicloids (Fig. 5B). In our previous study, oxytocin caused a 1.3-increase in the same assay6. These results suggest that cinnamic acid has almost the same level of hair growth-promoting effect as oxytocin. Oxytocin and cinnamic acid work through the same molecular mechanism of activating the oxytocin signaling pathway, but oxytocin binds to OXTR and cinnamic acid upregulates the expression of OXTR. Therefore, synergic effects of hair growth promotion can be expected by the combination of oxytocin and cinnamic acid. Oxytocin can be administered locally due to its short half-life (< 8 min) in blood24. However, due to its large molecular weight, its transdermal permeability is low, and approaches that stably activate the oxytocin signaling pathway are needed. Cinnamic acid is a stable, small molecule and has high transdermal permeability, and may reach other organs after application to the skin. Therefore, its side effects should be thoroughly investigated. Nevertheless, since both molecules are biomolecules safety concerns are expected to be low.

The most reliable in vitro model for evaluating hair growth-promoting effects is hair organ culture, in which human hair follicles are harvested from the scalp and cultured with drug candidates in vitro. However, the number of samples that can be harvested from humans is limited and the nature and hair cycle of individual hair follicles differ, making it challenging to obtain sufficient and reliable data. We developed an approach to prepare hair follicles in vitro (hair follicloids) that can regenerate hair shaft-like structures. Hair follicloids are prepared using cells isolated from multiple hair follicles, leading to a more uniform, prolific test system. Hair follicloids can be used to verify the efficacy of hair growth-promoting drugs by measuring the elongation of hair shaft-like structures, similar to conventional organ culture. In this study, we used hair follicloids to investigate the hair growth-promoting effects of cinnamic acid. However, in vivo studies are required to further investigate effects of transdermal dosing methods, concentrations, intervals, and side effects. In future, we plan to conduct such studies using mouse models of alopecia.

Cinnamomum cassia components and cinnamic acid derivatives have various functions. Cinnamomum cassia components (e.g. cinnamaldehyde, cinnamyl alcohol, and cinnamic acid) have a cinnamon scent and are used in cosmetics as fragrances 25,26. Ester derivatives of cinnamic acid (e.g. ethylhexyl methoxysilicate, isoamyl p-methoxysilicate, octocrylene, and cinoxate) have UV protective properties and are used in cosmetics as sunscreen27. In addition, cinnamic acid derivatives have antioxidant properties that may slow down the skin aging process27. Investigating the hair growth-promoting effects of these cinnamic acid derivatives may facilitate the development of a drug that combines the UV protection/anti-aging effects of hair follicles with hair growth-promoting effects. Notably, allergic dermatitis is one of the side effects of Cinnamomum cassia components and cinnamic acid derivatives. Cinnamaldehyde and cinnamyl alcohol are sensitizers of allergic dermatitis, thereby limiting their contents in cosmetics28,29. Therefore, the use of cinnamic acid derivatives necessitates consideration of adverse effects.

To the best of our knowledge, allergic effects have not been identified for the cinnamic acid used in this study. However, further studies are needed to confirm the side effects for the skin and other organs. Topical administration to the hair follicles may minimize side effects.

In conclusion, cinnamic acid activated DP cells and promoted hair growth in vitro via increase in OXTR expression. These findings encourage further research on the discovery of drugs targeting OXTR in patients with hair loss. Although the same cell source was used in this study, the efficacy of cinnamic acid should be evaluated in future using donor cells isolated from patients with multiple alopecias. In future studies, we intend to conduct a comprehensive analysis of gene expression using multiple donor cells from patients with alopecia.