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1.
J Invest Dermatol ; 141(4S): 1031-1040, 2021 04.
Article in English | MEDLINE | ID: mdl-33509633

ABSTRACT

In this review, we propose that telomere length dynamics play an important but underinvestigated role in the biology of the hair follicle (HF), a prototypic, cyclically remodeled miniorgan that shows an intriguing aging pattern in humans. Whereas the HF pigmentary unit ages quickly, its epithelial stem cell (ESC) component and regenerative capacity are surprisingly aging resistant. Telomerase-deficient mice with short telomeres display an aging phenotype of hair graying and hair loss that is attributed to impaired HF ESC mobilization. Yet, it remains unclear whether the function of telomerase and telomeres in murine HF biology translate to the human system. Therefore, we propose new directions for future telomere research of the human HF. Such research may guide the development of novel treatments for selected disorders of human hair growth or pigmentation (e.g., chemotherapy-induced alopecia, telogen effluvium, androgenetic alopecia, cicatricial alopecia, graying). It might also increase the understanding of the global role of telomeres in aging-related human disease.


Subject(s)
Aging/genetics , Hair Follicle/pathology , Stem Cells/pathology , Telomerase/metabolism , Telomere Shortening/genetics , Aging/drug effects , Aging/pathology , Animals , Hair Diseases/drug therapy , Hair Diseases/genetics , Hair Diseases/pathology , Hair Follicle/cytology , Hair Follicle/enzymology , Humans , Mice , Mice, Transgenic , Pigmentation Disorders/drug therapy , Pigmentation Disorders/genetics , Pigmentation Disorders/pathology , Stem Cells/enzymology , Telomerase/antagonists & inhibitors , Telomerase/genetics , Telomere Shortening/drug effects
2.
Biomed Res Int ; 2020: 2916104, 2020.
Article in English | MEDLINE | ID: mdl-33178821

ABSTRACT

Extractions from Phaeodactylum tricornutum have been widely studied and evaluated to various biological effects. The aim of this study was to investigate the promotional effect of P. tricornutum extract (PTE) on the ERK1/2 signaling pathway involved in hair follicle cell proliferation. In order to illuminate the enhancement of PTE on hair growth by promoting proliferation of hair follicle cells, the activities of human hair follicle outer root sheath cell (HFORSC), human hair follicle germinal matrix cells (HFGMC), and hair epithelial melanocytes (HEM) were observed under PET treatment. Levels of keratins, PKCζ, ERK1/2, and p38 MAPK in hair follicle cells were determined by Western blotting to illustrate the mechanisms of PTE effects on hair growth. Analyzed by GC-MS, the main polyunsaturated fatty acids which were 9.43% of total fatty acids in PTE were linolenic acid, linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid. Melanin content and tyrosinase activity in HEM were measured. The results showed that PTE exhibited remarkable enhancement on cell proliferation. Melanin production was inhibited by PTE treatment, while keratin-14, keratin-15, and keratin-17 levels on hair follicle cells were elevated at different concentrations. The promotions of ERK1/2 and p38 MAPK levels indicated that the ERK1/2 signaling pathway is involved in the proliferation of hair follicle cells. These results are the evidence that PTE potentially deserves further study as a new natural candidate for hair care applications.


Subject(s)
Diatoms/chemistry , Fatty Acids/pharmacology , Hair Follicle/cytology , Hair Follicle/enzymology , MAP Kinase Signaling System , Cell Proliferation/drug effects , Cell Survival/drug effects , Epithelial Cells/drug effects , Epithelial Cells/enzymology , Fatty Acids/chemistry , Humans , Keratins/metabolism , MAP Kinase Signaling System/drug effects , Melanins/biosynthesis , Melanocytes/drug effects , Melanocytes/enzymology , Monophenol Monooxygenase/metabolism , Protein Kinase C/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
3.
EMBO J ; 39(18): e104365, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32696520

ABSTRACT

Hair follicle stem cells (HFSCs) are maintained in a quiescent state until activated to grow, but the mechanisms that reactivate the quiescent HFSC reservoir are unclear. Here, we find that loss of Sirt7 in mice impedes hair follicle life-cycle transition from telogen to anagen phase, resulting in delay of hair growth. Conversely, Sirt7 overexpression during telogen phase facilitated HSFC anagen entry and accelerated hair growth. Mechanistically, Sirt7 is upregulated in HFSCs during the telogen-to-anagen transition, and HFSC-specific Sirt7 knockout mice (Sirt7f/f ;K15-Cre) exhibit a similar hair growth delay. At the molecular level, Sirt7 interacts with and deacetylates the transcriptional regulator Nfatc1 at K612, causing PA28γ-dependent proteasomal degradation to terminate Nfatc1-mediated telogen quiescence and boost anagen entry. Cyclosporin A, a potent calcineurin inhibitor, suppresses nuclear retention of Nfatc1, abrogates hair follicle cycle delay, and promotes hair growth in Sirt7-/- mice. Furthermore, Sirt7 is downregulated in aged HFSCs, and exogenous Sirt7 overexpression promotes hair growth in aged animals. These data reveal that Sirt7 activates HFSCs by destabilizing Nfatc1 to ensure hair follicle cycle initiation.


Subject(s)
Hair Follicle/enzymology , Sirtuins/metabolism , Stem Cells/enzymology , Aging/genetics , Aging/metabolism , Animals , Cellular Senescence/drug effects , Cyclosporine/pharmacology , Mice , Mice, Knockout , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Sirtuins/genetics
5.
J Cosmet Dermatol ; 18(6): 1860-1865, 2019 Dec.
Article in English | MEDLINE | ID: mdl-30770632

ABSTRACT

Several journal reports, reviews, and commentaries over the last 20-25 years have pointed out the controversy attached to 17ß-estradiol's inhibitory or stimulatory influence on hair follicle growth/cycling citing rodent (murine) and human results. While 17ß-estradiol is the most potent sex steroid hormone in the body and has almost equal affinity for estrogen receptor (ER) alpha (α) and beta (ß), there appears to be specific ER-mediated effects on scalp hair follicles/growth, etc. Additionally, the newly discovered G protein-coupled estrogen receptor (GPR30 or GPER) and the orphan receptor, estrogen-related receptor (ERR) gamma (γ), in skin and other tissue sites have potential impacts of how estrogens via these receptors may alter scalp hair characteristics, but this remains to be elucidated. Conversely, the negative impact of the 5α-reductase enzyme and its steroid product, 5α-dihydrotestosterone, on scalp hair growth is clear. Less clear is how 17ß-estradiol is stimulatory in some scalp hair studies, but inhibitory in others. This brief summary examines the potential influences of steroidogenesis via aromatase (estrogen biosynthesis) and 5α-reductase expression, their enzyme activities, and steroid products along with the concepts of how steroid acute regulatory protein (StAR) and estrone sulfate may be involved in the complex hormonal, cellular/molecular signaling cascade of the hair follicle in growth and cycling.


Subject(s)
Androgens/physiology , Estradiol/physiology , Estrogens/physiology , Hair Follicle/growth & development , Receptors, Estrogen/physiology , Animals , Hair Follicle/enzymology , Humans
6.
Dermatol Ther ; 31(6): e12741, 2018 11.
Article in English | MEDLINE | ID: mdl-30226287

ABSTRACT

Topical minoxidil is the only US FDA approved OTC drug for the treatment of androgenetic alopecia (AGA). Minoxidil is a pro-drug converted into its active form, minoxidil sulfate, by the sulfotransferase enzymes in the outer root sheath of hair follicles. Previously, we demonstrated that sulfotransferase activity in hair follicles predicts response to topical minoxidil in the treatment of AGA. In the human liver, sulfotransferase activity is significantly inhibited by salicylic acid. Low-dose OTC aspirin (75-81 mg), a derivative of salicylic acid, is used by millions of people daily for the prevention of coronary heart disease and cancer. It is not known whether oral aspirin inhibits sulfotransferase activity in hair follicles, potentially affecting minoxidil response in AGA patients. In the present study, we determined the follicular sulfotransferase enzymatic activity following 14 days of oral aspirin administration. In our cohort of 24 subjects, 50% were initially predicted to be responders to minoxidil. However, following 14 days of aspirin administration, only 27% of the subjects were predicted to respond to topical minoxidil. To the best of our knowledge, this is the first study to report the effect of low-dose daily aspirin use on the efficacy of topical minoxidil.


Subject(s)
Alopecia/drug therapy , Aspirin/administration & dosage , Enzyme Inhibitors/administration & dosage , Hair Follicle/drug effects , Minoxidil/administration & dosage , Prodrugs/administration & dosage , Sulfotransferases/antagonists & inhibitors , Administration, Cutaneous , Adult , Alopecia/diagnosis , Alopecia/physiopathology , Aspirin/adverse effects , Drug Interactions , Enzyme Inhibitors/adverse effects , Hair Follicle/enzymology , Hair Follicle/growth & development , Humans , Male , Minoxidil/analogs & derivatives , Minoxidil/metabolism , Prodrugs/metabolism , Risk Assessment , Sulfotransferases/metabolism , Treatment Outcome , Young Adult
7.
Int J Cosmet Sci ; 40(5): 516-524, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30222197

ABSTRACT

OBJECTIVE: Hair greying (i.e., canities) is a component of chronological ageing and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying. METHODS: Effect of the PTP20 on the enzymatic activity of catalase and the production of H2 O2 by Human Follicle Dermal Papilla Cells (HFDPC) was evaluated. Influence of PTP20 on the expression of melanocortin receptor-1 (MC1-R) and the production of melanin were investigated. Enzymatic activity of sirtuin 1 (SIRT1) after treatment with PTP20 was also determined. Ex vivo studies using human micro-dissected hairs allowed to visualize the effect of PTP20 on the expression in hair follicle of catalase, TRP-1, TRP-2, Melan-A, ASIP, and MC1-R. These investigations were completed by a clinical study on 15 human male volunteers suffering from premature canities. RESULTS: The in vitro and ex vivo studies revealed the capacity of the examined PTP20 peptide to enhance the expression of catalase and to decrease (30%) the intracellular level of H2 O2 . Moreover, PTP20 was shown to activate in vitro and ex vivo the melanogenesis process. In fact, an increase in the production of melanin was shown to be correlated with elevated expression of MC1-R, TRP-1, and Melan-A, and with the reduction in ASIP expression. A modulation on TRP-2 was also observed. The pivotal role of MC1-R was confirmed on protein expression analysed on volunteer's plucked hairs after 3 months of the daily application of lotion containing 10 ppm of PTP20 peptide. CONCLUSION: The current findings demonstrate the ability of the biomimetic PTP20 peptide to preserve the function of follicular melanocytes. The present results suggest potential cosmetic application of this newly designed agonist of α-MSH to promote hair pigmentation and thus, reduce the hair greying process.


Subject(s)
Aging , Hair Color/drug effects , Oligopeptides/pharmacology , alpha-MSH/agonists , Adolescent , Adult , Aged , Catalase/metabolism , Cells, Cultured , Female , HEK293 Cells , Hair Follicle/enzymology , Hair Follicle/metabolism , Humans , Male , Receptor, Melanocortin, Type 1/genetics , Sirtuin 1/metabolism , Transcriptional Activation , Young Adult
8.
J Biol Regul Homeost Agents ; 32(4): 937-940, 2018.
Article in English | MEDLINE | ID: mdl-30043580

ABSTRACT

Minoxidil is the only US FDA-approved topical drug for the treatment of female and male pattern hair loss. Previously, it was demonstrated that topical minoxidil is metabolized to its active metabolite, minoxidil sulfate, by sulfotransferase enzymes located in the outer root sheath of hair follicles. The expression of sulfotransferase in the scalp varies greatly between individuals, and this difference in expression explains the varied response to minoxidil treatment. Previously, we have demonstrated the clinical utility of detecting sulfotransferase in plucked hair follicles to predict minoxidil response in pattern hair loss patients. Typically, exogenous exposure to substrates affects the expression of the enzymatic system responsible for their metabolism. For example, Phase I metabolizing enzymes, such as the cytochrome P450 family of enzymes, are known to be up-regulated in the presence of xenobiotic substrates. However, it is not known if Phase II metabolizing enzymes, such as the sulfotransferase family of enzymes, are similarly affected by the presence of substrates. In this study, we recruited 120 subjects and analyzed their sulfotransferase enzymatic activity before and after treatment with topical minoxidil. Adjusting the results for biologic (within subject) variability, we discovered that the sulfotransferase enzymatic system expression is stable over the course of minoxidil treatment. To the best of our knowledge, this is the first study to demonstrate the stability of sulfotransferase, a Phase II metabolizing enzyme, over the course of minoxidil treatment.


Subject(s)
Hair Follicle/drug effects , Hair Follicle/enzymology , Minoxidil/metabolism , Minoxidil/therapeutic use , Sulfotransferases/metabolism , Administration, Topical , Adult , Alopecia/drug therapy , Female , Humans , Male , Middle Aged
9.
J Biol Regul Homeost Agents ; 31(4): 1049-1053, 2017.
Article in English | MEDLINE | ID: mdl-29254313

ABSTRACT

Topical minoxidil is the only topical drug approved by the US Food and Drug Administration (FDA) for the treatment of androgenetic alopecia. However, the exact mechanism by which minoxidil stimulates anagen phase and promotes hair growth is not fully understood. In the late telegen phase of the hair follicle growth cycle, stem cells located in the bulge region differentiate and re-enter anagen phase, a period of growth lasting 2-6 years. In androgenetic alopecia, the anagen phase is shortened and a progressive miniaturization of hair follicles occurs, eventually leading to hair loss. Several studies have demonstrated that minoxidil increases the amount of intracellular Ca2+, which has been shown to up-regulate the enzyme adenosine triphosphate (ATP) synthase. A recent study demonstrated that ATP synthase, independent of its role in ATP synthesis, promotes stem cell differentiation. As such, we propose that minoxidil induced Ca2+ influx can increase stem cell differentiation and may be a key factor in the mechanism by which minoxidil facilitates hair growth. Based on our theory, we provide a roadmap for the development of a new class of drugs for the treatment of androgenetic alopecia.


Subject(s)
Alopecia/drug therapy , Hair Follicle/drug effects , Minoxidil/therapeutic use , Mitochondria/drug effects , Mitochondrial Proton-Translocating ATPases/genetics , Stem Cells/drug effects , Vasodilator Agents/therapeutic use , Adult , Alopecia/enzymology , Alopecia/genetics , Alopecia/pathology , Calcium/metabolism , Cell Differentiation/drug effects , Gene Expression , Hair Follicle/enzymology , Hair Follicle/pathology , Humans , Ion Transport/drug effects , Male , Middle Aged , Mitochondria/enzymology , Mitochondrial Proton-Translocating ATPases/metabolism , Stem Cells/enzymology , Stem Cells/pathology , Up-Regulation
10.
Nat Cell Biol ; 19(9): 1017-1026, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28812580

ABSTRACT

Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.


Subject(s)
Cell Proliferation , Cellular Senescence , Glycolysis , Hair Follicle/enzymology , L-Lactate Dehydrogenase/metabolism , Lactic Acid/metabolism , Stem Cells/enzymology , Acrylates/pharmacology , Animals , Anion Transport Proteins/antagonists & inhibitors , Anion Transport Proteins/genetics , Anion Transport Proteins/metabolism , Cell Proliferation/drug effects , Cellular Senescence/drug effects , Female , Genotype , Glycolysis/drug effects , Hair Follicle/cytology , Hair Follicle/drug effects , Isoenzymes/deficiency , Isoenzymes/genetics , Isoenzymes/metabolism , L-Lactate Dehydrogenase/deficiency , L-Lactate Dehydrogenase/genetics , Lactate Dehydrogenase 5 , Male , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Membrane Transport Proteins/antagonists & inhibitors , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Monocarboxylic Acid Transporters , Phenotype , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction , Stem Cells/drug effects , Time Factors
11.
Toxicol Appl Pharmacol ; 329: 190-201, 2017 08 15.
Article in English | MEDLINE | ID: mdl-28601433

ABSTRACT

In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and ß-naphthoflavone (ßNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients.


Subject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Hair Follicle/enzymology , Keratinocytes/enzymology , Xenobiotics/metabolism , Basic Helix-Loop-Helix Transcription Factors/agonists , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cells, Cultured , Cytochrome P-450 Enzyme Inducers/pharmacology , Cytochrome P-450 Enzyme System/genetics , Enzyme Induction , Glutathione Transferase/biosynthesis , Glutathione Transferase/genetics , Hair Follicle/cytology , Hair Follicle/drug effects , Humans , Isoenzymes , Keratinocytes/drug effects , Kinetics , Ligands , Metabolic Detoxication, Phase I , Metabolic Detoxication, Phase II , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/metabolism , Substrate Specificity , Sulfotransferases/biosynthesis , Sulfotransferases/genetics
12.
Molecules ; 22(1)2017 Jan 14.
Article in English | MEDLINE | ID: mdl-28098826

ABSTRACT

PAK1 (p21-activated kinase 1) is an emerging target for the treatment of hair loss (alopecia) and cancer; therefore, the search for PAK1 blockers to treat these PAK1-dependent disorders has received much attention. In this study, we evaluated the anti-alopecia and anticancer effects of PAK1 inhibitors isolated from Alpinia zerumbet (alpinia) in cell culture. The bioactive compounds isolated from alpinia were found to markedly promote hair cell growth. Kaempferol-3-O-ß-d-glucuronide (KOG) and labdadiene, two of the isolated compounds, increased the proliferation of human follicle dermal papilla cells by approximately 117%-180% and 132%-226%, respectively, at 10-100 µM. MTD (2,5-bis(1E,3E,5E)-6-methoxyhexa-1,3,5-trien-1-yl)-2,5-dihydrofuran) and TMOQ ((E)-2,2,3,3-tetramethyl-8-methylene-7-(oct-6-en-1-yl)octahydro-1H-quinolizine) showed growth-promoting activity around 164% and 139% at 10 µM, respectively. The hair cell proliferation induced by these compounds was significantly higher than that of minoxidil, a commercially available treatment for hair loss. Furthermore, the isolated compounds from alpinia exhibited anticancer activity against A549 lung cancer cells with IC50 in the range of 67-99 µM. Regarding the mechanism underlying their action, we hypothesized that the anti-alopecia and anticancer activities of these compounds could be attributed to the inhibition of the oncogenic/aging kinase PAK1.


Subject(s)
Alpinia/chemistry , Antineoplastic Agents/pharmacology , Diterpenes/pharmacology , Epithelial Cells/drug effects , Glucuronides/pharmacology , Kaempferols/pharmacology , Protein Kinase Inhibitors/pharmacology , p21-Activated Kinases/genetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Diterpenes/chemistry , Diterpenes/isolation & purification , Epithelial Cells/cytology , Epithelial Cells/enzymology , Flowers/chemistry , Furans/chemistry , Furans/isolation & purification , Furans/pharmacology , Gene Expression , Glucuronides/chemistry , Glucuronides/isolation & purification , Hair Follicle/cytology , Hair Follicle/drug effects , Hair Follicle/enzymology , Humans , Kaempferols/chemistry , Kaempferols/isolation & purification , Minoxidil/pharmacology , Plant Leaves/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/isolation & purification , Quinolizines/chemistry , Quinolizines/isolation & purification , Quinolizines/pharmacology , Rhizome/chemistry , p21-Activated Kinases/antagonists & inhibitors , p21-Activated Kinases/metabolism
13.
J Biol Chem ; 291(30): 15602-13, 2016 07 22.
Article in English | MEDLINE | ID: mdl-27226633

ABSTRACT

Recent studies using knock-out mice for various secreted phospholipase A2 (sPLA2) isoforms have revealed their non-redundant roles in diverse biological events. In the skin, group IIF sPLA2 (sPLA2-IIF), an "epidermal sPLA2" expressed in the suprabasal keratinocytes, plays a fundamental role in epidermal-hyperplasic diseases such as psoriasis and skin cancer. In this study, we found that group IIE sPLA2 (sPLA2-IIE) was expressed abundantly in hair follicles and to a lesser extent in basal epidermal keratinocytes in mouse skin. Mice lacking sPLA2-IIE exhibited skin abnormalities distinct from those in mice lacking sPLA2-IIF, with perturbation of hair follicle ultrastructure, modest changes in the steady-state expression of a subset of skin genes, and no changes in the features of psoriasis or contact dermatitis. Lipidomics analysis revealed that sPLA2-IIE and -IIF were coupled with distinct lipid pathways in the skin. Overall, two skin sPLA2s, hair follicular sPLA2-IIE and epidermal sPLA2-IIF, play non-redundant roles in distinct compartments of mouse skin, underscoring the functional diversity of multiple sPLA2s in the coordinated regulation of skin homeostasis and diseases.


Subject(s)
Dermatitis, Contact/enzymology , Gene Expression Regulation, Enzymologic , Group II Phospholipases A2/biosynthesis , Hair Follicle/enzymology , Psoriasis/enzymology , Animals , Dermatitis, Contact/genetics , Dermatitis, Contact/pathology , Epidermis/enzymology , Epidermis/pathology , Group II Phospholipases A2/genetics , Hair Follicle/pathology , Mice , Mice, Knockout , Psoriasis/genetics , Psoriasis/pathology
14.
J Pathol ; 239(3): 374-83, 2016 07.
Article in English | MEDLINE | ID: mdl-27126290

ABSTRACT

The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Subject(s)
Alkaline Ceramidase/metabolism , Alopecia/enzymology , Ceramides/metabolism , Energy Metabolism , Homeostasis , Alkaline Ceramidase/genetics , Alopecia/physiopathology , Animals , Cell Differentiation , Epidermis/abnormalities , Epidermis/enzymology , Female , Hair Follicle/abnormalities , Hair Follicle/enzymology , Humans , Keratinocytes/enzymology , Keratinocytes/physiology , Male , Mice , Mice, Inbred C57BL , Pituitary Gland/abnormalities , Pituitary Gland/enzymology , Sebaceous Glands/abnormalities , Sebaceous Glands/enzymology , Skin/enzymology , Skin Abnormalities , Sphingolipids/metabolism
15.
J Biol Chem ; 291(6): 2577-82, 2016 Feb 05.
Article in English | MEDLINE | ID: mdl-26719335

ABSTRACT

The membrane-anchored serine prostasin (CAP1/PRSS8) is essential for barrier acquisition of the interfollicular epidermis and for normal hair follicle development. Consequently, prostasin null mice die shortly after birth. Prostasin is found in two forms in the epidermis: a one-chain zymogen and a two-chain proteolytically active form, generated by matriptase-dependent activation site cleavage. Here we used gene editing to generate mice expressing only activation site cleavage-resistant (zymogen-locked) endogenous prostasin. Interestingly, these mutant mice displayed normal interfollicular epidermal development and postnatal survival, but had defects in whisker and pelage hair formation. These findings identify two distinct in vivo functions of epidermal prostasin: a function in the interfollicular epidermis, not requiring activation site cleavage, that can be mediated by the zymogen-locked version of prostasin and a proteolysis-dependent function of activated prostasin in hair follicles, dependent on zymogen conversion by matriptase.


Subject(s)
Enzyme Precursors/metabolism , Hair Follicle/enzymology , Serine Endopeptidases/metabolism , Animals , Enzyme Activation , Enzyme Precursors/genetics , Mice , Serine Endopeptidases/genetics
17.
Int J Mol Med ; 36(4): 1088-96, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26311045

ABSTRACT

Human placental extract (HPE) is widely used in Korea to relieve fatigue. However, its effects on human dermal papilla cells (hDPCs) remain unknown. In the present study, in an effort to develop novel therapies to promote hair growth, we screened HPE. We demonstrate that HPE has hair growth­promoting activities and induces ß­catenin expression through the inhibition of glycogen synthase kinase­3ß (GSK­3ß) by phosphorylation in hDPCs. Treatment with HPE significantly increased the viability of the hDPCs in a concentration­dependent manner, as shown by bromodeoxyuridine (BrdU) assay. HPE also significantly increased the alkaline phosphatase (ALP) expression levels. The increased ß­catenin levels and the inhibition of GSK­3ß (Ser9) by phosphorylation suggested that HPE promoted the hair-inductive capacity of hDPCs. We compared the effects of treatment with HPE alone and treatment with HPE in conjunction with minoxidil (MXD). We found that HPE plus MXD effectively inhibited GSK­3ß by phosphorylation (Ser9) in the hDPCs. Moreover, we demonstrated that HPE was effective in inducing root hair elongation in rat vibrissa hair follicles, and that treatment with HPE led to a delay in catagen progression. Overall, our findings suggest that HPE promotes hair growth and may thus provide the basis of a novel therapeutic strategy for the clinical treatment of hair loss.


Subject(s)
Complex Mixtures/pharmacology , Dermis/enzymology , Glycogen Synthase Kinase 3/metabolism , Hair Follicle/enzymology , Placenta/chemistry , Signal Transduction/drug effects , Animals , Complex Mixtures/chemistry , Dermis/cytology , Female , Glycogen Synthase Kinase 3 beta , Hair Follicle/cytology , Humans , Hypotrichosis/drug therapy , Hypotrichosis/enzymology , Pregnancy , Rats
18.
Acta Histochem ; 117(8): 798-802, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26257011

ABSTRACT

Lysozyme is a well-known antimicrobial peptide that exists widely in mammalian skin and it is also expressed by pilosebaceous units. However, the exact location of lysozyme in hair follicles and whether it exerts any direct effects on hair follicle growth are unclear. To determine whether lysozyme affected hair growth in vitro, micro-dissected mouse vibrissae follicles (VFs) were treated in serum-free organ culture for 3 days with lysozyme (1-10µg/ml). After that, the effects of lysozyme on dermal papilla (DP) cells were also investigated. Lysozyme was mainly identified in DP and dermal sheath regions of VF by immunochemistry. In addition, 5-10µg/ml lysozyme had a promoting effect on shaft production. It was also associated with significant proliferation of matrix keratinocytes by immunofluorescence observation. Furthermore, lysozyme promoted hair growth by increasing the levels of alkaline phosphatase and lymphoid enhancer factor 1 in DP, as determined by Western blotting. These results indicate that lysozyme is a promoter of VF growth via enhancing the hair-inductive capacity of DP cells during organ culture.


Subject(s)
Hair Follicle/enzymology , Muramidase/physiology , Vibrissae/enzymology , Animals , Female , Hair Follicle/cytology , Hair Follicle/growth & development , Mice, Inbred C57BL , Muramidase/pharmacology , Tissue Culture Techniques , Vibrissae/growth & development
19.
Reproduction ; 150(4): 323-30, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26152195

ABSTRACT

Genetic lineage tracing has been used extensively in developmental biology. Many transcription factors expressed in sperm may induce Cre-mediated loxP recombination during early zygote development. In this study, we investigated the effect of sperm-expressed Cre on cell type-specific Cre-mediated loxP recombination in fate-mapping models of Tbx18+ progenitor cells. We found the recombination frequency in a reverse mating (RM) lineage was inconsistent with a normal Mendelian distribution. However, the recombination frequency in a positive mating (PM) lineage agreed with a Mendelian distribution. In the PM lineage, LacZ and EYFP were expressed in specific locations, such as the limb buds, heart, and hair follicles. Therefore, the reporter genes accurately and reliably traced cell differentiation in the PM lineage. In contrast, EYFP and LacZ were expressed throughout the embryo in the RM lineage. Thus, the reporter genes did not trace cell differentiation specifically in the RM lineage. Furthermore, Tbx18 mRNA and protein were expressed in the testicles of male mice, but almost no Tbx18 expression was detected in the ovaries of female mice. Similarly, reporter genes and Tbx18 were coexpressed in the seminiferous tubules and sperm cells of testicles. These results revealed that Cre-loxP-mediated pre-recombination in zygotes is due to Tbx18 expressed in testicle sperm cells when Cre is transmitted paternally. Our results indicate that Cre-mediated specific recombination in fate-mapping models of sperm-expressed genes may be influenced by the paternal origin of Cre. Therefore, a careful experimental design is critical when using the Cre-loxP system to trace spatial, temporal or tissue-specific fates.


Subject(s)
Spermatozoa/metabolism , Transcription Factors/genetics , Animals , Cell Differentiation/genetics , Cell Lineage/genetics , Female , Genes, Reporter , Hair Follicle/enzymology , Hair Follicle/metabolism , Heart/embryology , Limb Buds/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Biological , Myocardium/metabolism , Recombination, Genetic , Stem Cells , T-Box Domain Proteins/genetics
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