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1.
Sci Rep ; 11(1): 20761, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675331

RESUMO

Hair follicles (HFs) are unique, multi-compartment, mini-organs that cycle through phases of active hair growth and pigmentation (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Anagen HFs have high demands for energy and biosynthesis precursors mainly fulfilled by aerobic glycolysis. Histochemistry reports the outer root sheath (ORS) contains high levels of glycogen. To investigate a functional role for glycogen in the HF we quantified glycogen by Periodic-Acid Schiff (PAS) histomorphometry and colorimetric quantitative assay showing ORS of anagen VI HFs contained high levels of glycogen that decreased in catagen. qPCR and immunofluorescence microscopy showed the ORS expressed all enzymes for glycogen synthesis and metabolism. Using human ORS keratinocytes (ORS-KC) and ex vivo human HF organ culture we showed active glycogen metabolism by nutrient starvation and use of a specific glycogen phosphorylase (PYGL) inhibitor. Glycogen in ORS-KC was significantly increased by incubation with lactate demonstrating a functional Cori cycle. Inhibition of PYGL significantly stimulated the ex vivo growth of HFs and delayed onset of catagen. This study defines translationally relevant and therapeutically targetable new features of HF metabolism showing that human scalp HFs operate an internal Cori cycle, synthesize glycogen in the presence of lactate and modulate their growth via PYGL activity.

2.
Exp Dermatol ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587317

RESUMO

It has long been known that there is a special affinity of psoriasis for the scalp: Here, it occurs most frequently, lesions terminate sharply in frontal skin beyond the hair line and are difficult to treat. Yet, surprisingly, scalp psoriasis only rarely causes alopecia, even though the pilosebaceous unit clearly is affected. Here, we systematically explore the peculiar, insufficiently investigated connection between psoriasis and growing (anagen) terminal scalp hair follicles (HFs), with emphasis on shared regulatory mechanism and therapeutic targets. Interestingly, several drugs and stressors that can trigger/aggravate psoriasis can inhibit hair growth (e.g. beta-blockers, chloroquine, carbamazepine, interferon-alpha, perceived stress). Instead, several anti-psoriatic agents can stimulate hair growth (e.g. cyclosporine, glucocorticoids, dithranol, UV irradiation), while skin/HF trauma (Köbner phenomenon/depilation) favours the development of psoriatic lesions and induces anagen in "quiescent" (telogen) HFs. On this basis, we propose two interconnected working models: (a) the existence of a bidirectional "hair follicle-psoriasis axis," along which keratinocytes of anagen scalp HFs secrete signals that favour the development and maintenance of psoriatic scalp lesions and respond to signals from these lesions, and (b) that anagen induction and psoriatic lesions share molecular "switch-on" mechanisms, which invite pharmacological targeting, once identified. Therefore, we advocate a novel, cross-fertilizing and integrative approach to psoriasis and hair research that systematically characterizes the "HF-psoriasis axis," focused on identification and therapeutic targeting of selected, shared signalling pathways in the future management of both, psoriasis and hair growth disorders.

3.
J Autoimmun ; 124: 102711, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34479087

RESUMO

Murine γδT-cells have stress-surveillance functions and are implicated in autoimmunity. Yet, whether human γδT-cells are also stress sentinels and directly promote autoimmune responses in the skin is unknown. Using a novel (mini-)organ assay, we tested if human dermis resident γδT-cells can recognize stressed human scalp hair follicles (HFs) to promote an alopecia areata (AA)-like autoimmune response. Accordingly, we show that γδT-cells from healthy human scalp skin are activated (CD69+), up-regulate the expression of NKG2D and IFN-γ, and become cytotoxic when co-cultured with autologous stressed HFs ex vivo. These autologous γδT-cells induce HF immune privilege collapse, dystrophy, and premature catagen, i.e. three hallmarks of the human autoimmune HF disorder, AA. This is mediated by CXCL12, MICA, and in part by IFN-γ and CD1d. In conclusion, human dermal γδT-cells exert physiological stress-sentinel functions in human skin, where their excessive activity can promote autoimmunity towards stressed HFs that overexpress CD1d, CXCL12, and/or MICA.

4.
Bioessays ; 43(10): e2100005, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34486144

RESUMO

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under-investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune-modulatory properties, including the creation of an immunoinhibitory, immune-privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of yeast and bacterial species, along with increasing proinflammatory sebum by-products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune-microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs.


Assuntos
Caspa , Dermatite Seborreica , Folículo Piloso , Humanos , Inflamação , Couro Cabeludo
5.
Bioessays ; 43(10): e2100126, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34486148

RESUMO

MPZL3 is a nuclear-encoded, mitochondrially localized, immunoglobulin-like V-type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling hub that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology.


Assuntos
Folículo Piloso , Mitocôndrias , Animais , Proteínas CLOCK , Diferenciação Celular , Ritmo Circadiano , Proteínas de Membrana , Camundongos , Camundongos Knockout , Mitocôndrias/genética
8.
Biomedicines ; 9(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069454

RESUMO

Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-ß and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.

9.
Biol Rev Camb Philos Soc ; 96(6): 2573-2583, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34145718

RESUMO

In organ regeneration, the regulatory logic at a systems level remains largely unclear. For example, what defines the quantitative threshold to initiate regeneration, and when does the regeneration process come to an end? What leads to the qualitatively different responses of regeneration, which restore the original structure, or to repair which only heals a wound? Here we discuss three examples in skin regeneration: epidermal recovery after radiation damage, hair follicle fate choice after chemotherapy damage, and wound-induced feather regeneration. We propose that the molecular regulatory circuitry is of paramount significance in organ regeneration. It is conceivable that defects in these controlling pathways may lead to failed regeneration and/or organ renewal, and understanding the underlying logic could help to identify novel therapeutic strategies.

10.
Elife ; 102021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34155974

RESUMO

Background: Hair greying is a hallmark of aging generally believed to be irreversible and linked to psychological stress. Methods: Here, we develop an approach to profile hair pigmentation patterns (HPPs) along individual human hair shafts, producing quantifiable physical timescales of rapid greying transitions. Results: Using this method, we show white/grey hairs that naturally regain pigmentation across sex, ethnicities, ages, and body regions, thereby quantitatively defining the reversibility of greying in humans. Molecularly, grey hairs upregulate proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining HPP profiling and proteomics on single hairs, we also report hair greying and reversal that can occur in parallel with psychological stressors. To generalize these observations, we develop a computational simulation, which suggests a threshold-based mechanism for the temporary reversibility of greying. Conclusions: Overall, this new method to quantitatively map recent life history in HPPs provides an opportunity to longitudinally examine the influence of recent life exposures on human biology. Funding: This work was supported by the Wharton Fund and NIH grants GM119793, MH119336, and AG066828 (MP).


Assuntos
Envelhecimento , Mapeamento Cromossômico , Cor de Cabelo/genética , Estresse Psicológico , Adolescente , Adulto , Criança , Cabelo/química , Humanos , Pessoa de Meia-Idade , Adulto Jovem
11.
J Invest Dermatol ; 141(12): 2957-2965.e5, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34116066

RESUMO

UDP-GlcNAc-1-phosphotransferase, a product of two separate genes (GNPTAB, GNPTG), is essential for the sorting and transportation of lysosomal enzymes to lysosomes. GNPTAB gene defects cause extracellular missorting of lysosomal enzymes resulting in lysosomal storage diseases, namely mucolipidosis type II and mucolipidosis type III alpha/beta, which is associated with hair discoloration. Yet, the physiological functions of GNPTAB in the control of hair follicle (HF) pigmentation remain unknown. To elucidate these, we have silenced GNPTAB in organ-cultured human HFs as a human ex vivo model for mucolipidosis type II. GNPTAB silencing profoundly inhibited intrafollicular melanin production, the correct sorting of melanosomes, tyrosinase activity, and HMB45 expression in the HF pigmentary unit and altered HF melanocyte morphology in situ. In isolated primary human HF melanocytes, GNPTAB knockdown significantly reduced melanogenesis, tyrosinase activity, and correct tyrosinase protein sorting as well as POMC expression and caused the expected lysosomal enzyme missorting in vitro. Moreover, transgenic mice overexpressing an inserted missense mutation corresponding to that seen in human mucolipidosis type II and mucolipidosis type III alpha/beta showed significantly reduced HF pigmentation, thus corroborating the in vivo relevance of our ex vivo and in vitro findings in the human system. This identifies GNPTAB as a clinically important enzymatic control of human HF pigmentation, likely by directly controlling tyrosinase sorting and POMC transcription in HF melanocytes.

12.
Math Med Biol ; 38(3): 314-332, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34109398

RESUMO

The goal of patient-specific treatment of diseases requires a connection between clinical observations with models that are able to accurately predict the disease progression. Even when realistic models are available, it is very difficult to parameterize them and often parameter estimates that are made using early time course data prove to be highly inaccurate. Inaccuracies can cause different predictions, especially when the progression depends sensitively on the parameters. In this study, we apply a Bayesian data assimilation method, where the data are incorporated sequentially, to a model of the autoimmune disease alopecia areata that is characterized by distinct spatial patterns of hair loss. Using synthetic data as simulated clinical observations, we show that our method is relatively robust with respect to variations in parameter estimates. Moreover, we compare convergence rates for parameters with different sensitivities, varying observational times and varying levels of noise. We find that this method works better for sparse observations, sensitive parameters and noisy observations. Taken together, we find that our data assimilation, in conjunction with our biologically inspired model, provides directions for individualized diagnosis and treatments.


Assuntos
Alopecia em Áreas , Doenças Autoimunes , Alopecia em Áreas/epidemiologia , Teorema de Bayes , Progressão da Doença , Humanos
13.
J Invest Dermatol ; 141(9): 2178-2188.e6, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33984347

RESUMO

Maintaining tissue homeostasis depends on a balance between cell proliferation, differentiation, and apoptosis. Within the epidermis, the levels of the polyamines putrescine, spermidine, and spermine are altered in many different skin conditions, yet their role in epidermal tissue homeostasis is poorly understood. We identify the polyamine regulator, Adenosylmethionine decarboxylase 1 (AMD1), as a crucial regulator of keratinocyte (KC) differentiation. AMD1 protein is upregulated on differentiation and is highly expressed in the suprabasal layers of the human epidermis. During KC differentiation, elevated AMD1 promotes decreased putrescine and increased spermine levels. Knockdown or inhibition of AMD1 results in reduced spermine levels and inhibition of KC differentiation. Supplementing AMD1-knockdown KCs with exogenous spermidine or spermine rescued aberrant differentiation. We show that the polyamine shift is critical for the regulation of key transcription factors and signaling proteins that drive KC differentiation, including KLF4 and ZNF750. These findings show that human KCs use controlled changes in polyamine levels to modulate gene expression to drive cellular behavior changes. Modulation of polyamine levels during epidermal differentiation could impact skin barrier formation or can be used in the treatment of hyperproliferative skin disorders.

15.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803422

RESUMO

Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not thoroughly understood. Because the key stress-mediating neurohormone, corticotropin-releasing hormone (CRH), induces human skin MC degranulation, we hypothesized that CRH may be a key player in stress-aggravated nasal allergy. In the current study, we probed this hypothesis in human nasal mucosa MCs (hM-MCs) in situ using nasal polyp organ culture and tested whether CRH is required for murine M-MC activation by perceived stress in vivo. CRH stimulation significantly increased the number of hM-MCs, stimulated both their degranulation and proliferation ex vivo, and increased stem cell factor (SCF) expression in human nasal mucosa epithelium. CRH also sensitized hM-MCs to further CRH stimulation and promoted a pro-inflammatory hM-MC phenotype. The CRH-induced increase in hM-MCs was mitigated by co-administration of CRH receptor type 1 (CRH-R1)-specific antagonist antalarmin, CRH-R1 small interfering RNA (siRNA), or SCF-neutralizing antibody. In vivo, restraint stress significantly increased the number and degranulation of murine M-MCs compared with sham-stressed mice. This effect was mitigated by intranasal antalarmin. Our data suggest that CRH is a major activator of hM-MC in nasal mucosa, in part via promoting SCF production, and that CRH-R1 antagonists such as antalarmin are promising candidate therapeutics for nasal mucosa neuroinflammation induced by perceived stress.


Assuntos
Degranulação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Mastócitos/metabolismo , Mucosa Nasal/metabolismo , Rinite Alérgica/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Rinite Alérgica/patologia
17.
Trends Pharmacol Sci ; 42(5): 316-328, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33752908

RESUMO

The immunophilin ligand, cyclosporine A (CsA), which inhibits nuclear factor of activated T cells (NFAT) activity, is a cornerstone of immunosuppressive therapy. Yet, the molecular basis of its prominent, nonimmunosuppression-related adverse skin effects, namely drug-induced excessive hair growth (hypertrichosis), is insufficiently understood. Here, we argue that analysis of these adverse effects can uncover clinically important, previously unknown mechanisms of CsA and identify new molecular targets and lead compounds for therapeutic intervention. We exemplify this through our recent discovery that CsA suppresses the potent Wnt inhibitor, secreted frizzled related protein (SFRP)1, in human hair follicles, thereby promoting hair growth and causing hypertrichosis. On this basis, we advocate a new focus on deciphering the molecular basis of the adverse effects of CsA in suitable human model systems as a lead to developing novel therapeutics.


Assuntos
Ciclosporina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ciclosporina/efeitos adversos , Humanos , Imunossupressores , Ligantes , Fatores de Transcrição NFATC
19.
Exp Dermatol ; 30(5): 645-651, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33548088

RESUMO

Human scalp hair follicles (HF) preferentially engage in glycolysis followed by lactate production in the presence of oxygen (i.e. the Warburg effect). Through the spatiotemporally controlled expression of key metabolic proteins, we hypothesise that the Warburg effect and other HF metabolic programmes are compartmentalised by region in order to regulate regional cell fate and phenotypes, such as epithelial stem cell quiescence in the bulge or keratinocyte proliferation in the hair matrix. We further propose that metabolic conditions in the HF are organised in accordance with the lactate shuttle, hypothesised to occur in other tissue systems and tumours, but never before described in the HF. Specifically, we argue that lactate is produced and exported by glycolytic GLUT1+ lower outer root sheath (ORS) keratinocytes. We further propose that lactate is then utilised by neighbouring highly proliferative matrix keratinocytes to fuel oxidative metabolism via MCT1-mediated uptake. Furthermore, as lactate has been described to be immunomodulatory, its production and accumulation could enhance immune tolerance in the HF bulb. Here we delineate how to experimentally probe this hypothesis, define major open questions and present preliminary immunohistological evidence in support of metabolic compartmentalisation and lactate shuttling. Overall, we argue that basic and translational hair research needs to rediscover the importance of lactate in human HF biology, well beyond its recognised role in murine HF epithelial stem cells, and should explore how HF metabolism can be therapeutically targeted to modulate hair growth and the immunological HF microenvironment as a novel strategy for managing hair loss disorders.

20.
Exp Dermatol ; 30(4): 479-493, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33523535

RESUMO

The endocannabinoid system (ECS) regulates multiple aspects of human epithelial physiology, including inhibition/stimulation of keratinocyte proliferation/apoptosis, respectively. Yet, how the ECS impacts on human adult epithelial stem cell (eSC) functions remains unknown. Scalp hair follicles (HFs) offer a clinically relevant, prototypic model system for studying this directly within the native human stem cell niche. Here, we show in organ-cultured human HFs that, unexpectedly, selective activation of cannabinoid receptor-1 (CB1)-mediated signalling via the MAPK (MEK/Erk 1/2) and Akt pathways significantly increases the number and proliferation of cytokeratin CK15+ or CK19+ human HF bulge eSCs in situ, and enhances CK15 promoter activity in situ. In striking contrast, CB1-stimulation promotes apoptosis in the differentiated progeny of these eSCs (CK6+ HF keratinocytes). Instead, intrafollicular CB1 gene knockdown or CB1 antagonist treatment significantly reduces human HF eSCs numbers and stimulates their apoptosis, while CB1 knockout mice exhibit a reduced bulge eSCs pool in vivo. This identifies "tonic" CB1 signalling as a required survival stimulus for adult human HF eSCs within their niche. This novel concept must be taken into account whenever the human ECS is targeted therapeutically.

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