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      L-Cystine-Containing Hair-Growth Formulation Supports Protection, Viability, and Proliferation of Keratinocytes

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          Abstract

          Purpose

          Clinical studies have confirmed that the hair-growth-promoting effect of approved oral drug combinations is beneficial for the treatment of diffuse telogen effluvium, which is characterized by the excessive loss of telogen club hairs. Since data elucidating the mode of action of such combinations are limited, our study focused on the identification of cellular processes potentially supporting the treatment of hair loss.

          Materials and Methods

          A minimal growth culture system (MGM) was used to mimic in vitro the reduced activity of human hair follicular keratinocytes (HHFKs). The effect of four core compounds (L-cystine, thiamine, calcium D-pantothenate, and folic acid) of a marketed oral combination (Panto[vi]gar ®), which are approved for the treatment of diffuse hair loss, was examined by comparing HHFKs cultured either with or without the compounds. After determining their impact on metabolic activity and proliferation, we conducted a comparative whole-genome gene expression study with subsequent functional grouping of differentially expressed genes to identify cellular processes influenced by the tested compounds.

          Results

          The four core compounds of an oral hair-growth formulation enhanced proliferation and metabolic activity of HHFKs compared to HHFKs cultivated in MGM only. Functional grouping of differentially expressed genes confirmed the regulation of cell cycle-/proliferation-associated genes (cdk1, HJURP) and revealed regulation of cell death- and oxidative stress-associated gene groups. A supportive effect of the compounds on cell viability was demonstrated by lower sensitivity to solar-simulated UV-radiation and increased protection against oxidative stress. We established a central role for L-cystine, as changes in the expression of the anti-oxidative gene hmox1 were L-cystine-dependent. However, to reach a maximal stimulating effect on proliferation, the combination of all four compounds was necessary.

          Conclusion

          The tested compound combination had positive effects on metabolic activity, cell viability, and proliferation of keratinocytes. Furthermore, this study suggested that L-cystine primarily contributes to the observed protection against endogenous oxidative stress.

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          Most cited references29

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          Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.

          Inconsistent with the view that hair follicle stem cells reside in the matrix area of the hair bulb, we found that label-retaining cells exist exclusively in the bulge area of the mouse hair follicle. The bulge consists of a subpopulation of outer root sheath cells located in the midportion of the follicle at the arrector pili muscle attachment site. Keratinocytes in the bulge area are relatively undifferentiated ultrastructurally. They are normally slow cycling, but can be stimulated to proliferate transiently by TPA. Located in a well-protected and nourished environment, these cells mark the lower end of the "permanent" portion of the follicle. Our findings, plus a reevaluation of the literature, suggest that follicular stem cells reside in the bulge region, instead of the lower bulb. This new view provides insights into hair cycle control and the possible involvement of hair follicle stem cells in skin carcinogenesis.
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            The hair follicle as a dynamic miniorgan.

            Hair is a primary characteristic of mammals, and exerts a wide range of functions including thermoregulation, physical protection, sensory activity, and social interactions. The hair shaft consists of terminally differentiated keratinocytes that are produced by the hair follicle. Hair follicle development takes place during fetal skin development and relies on tightly regulated ectodermal-mesodermal interactions. After birth, mature and actively growing hair follicles eventually become anchored in the subcutis, and periodically regenerate by spontaneously undergoing repetitive cycles of growth (anagen), apoptosis-driven regression (catagen), and relative quiescence (telogen). Our molecular understanding of hair follicle biology relies heavily on mouse mutants with abnormalities in hair structure, growth, and/or pigmentation. These mice have allowed novel insights into important general molecular and cellular processes beyond skin and hair biology, ranging from organ induction, morphogenesis and regeneration, to pigment and stem cell biology, cell proliferation, migration and apoptosis. In this review, we present basic concepts of hair follicle biology and summarize important recent advances in the field.
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              Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP.

              The centromere is responsible for accurate chromosome segregation. Mammalian centromeres are specified epigenetically, with all active centromeres containing centromere-specific chromatin in which CENP-A replaces histone H3 within the nucleosome. The proteins responsible for assembly of human CENP-A into centromeric nucleosomes during the G1 phase of the cell cycle are shown here to be distinct from the chromatin assembly factors previously shown to load other histone H3 variants. Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly.
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                Author and article information

                Journal
                Clin Cosmet Investig Dermatol
                Clin Cosmet Investig Dermatol
                CCID
                ccid
                Clinical, Cosmetic and Investigational Dermatology
                Dove
                1178-7015
                03 August 2020
                2020
                : 13
                : 499-510
                Affiliations
                [1 ]Cell Biology Unit, University Medical Center Mainz , Mainz 55131, Germany
                [2 ]Pharmaceutical Development, Merz Pharmaceuticals GmbH , Frankfurt Am Main 60438, Germany
                [3 ]Co.faktor GmbH , Berlin 10178, Germany
                Author notes
                Correspondence: Harry F Abts Merz Pharmaceuticals GmbH , 60438, Frankfurt Am Main, Alfred-Wegener-Straße 2, FIZ 2, F08.10.014, Frankfurt Am Main60438, GermanyTel +49 69 15 03 1324Fax +49 69 15 03 9152 Email Harry.Abts@merz.com
                Author information
                http://orcid.org/0000-0001-5295-4699
                Article
                254720
                10.2147/CCID.S254720
                7413702
                32801826
                424bd404-dcfb-4956-86c8-b539b37c8bf1
                © 2020 Riegel et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 17 April 2020
                : 05 June 2020
                Page count
                Figures: 5, References: 34, Pages: 12
                Categories
                Original Research

                Dermatology
                telogen effluvium,protection,genetic analysis,keratinocytes,oxidative stress
                Dermatology
                telogen effluvium, protection, genetic analysis, keratinocytes, oxidative stress

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