RESUMO
Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.
Assuntos
Vesícula , Folículo Piloso , Adulto , Vesícula/genética , Células Epidérmicas , Epiderme , Humanos , Pele , Células-TroncoRESUMO
Revertant mosaicism (RM) is a phenomenon in which inherited mutations are spontaneously corrected in somatic cells. RM occurs in some congenital skin diseases, but genetic validation of RM in clinically revertant skin has been challenging, especially when homologous recombination (HR) is responsible for RM. Here, we introduce nanopore Cas9-targeted sequencing (nCATS) for identifying HR in clinically revertant skin. We took advantage of compound heterozygous COL7A1 mutations in a patient with recessive dystrophic epidermolysis bullosa who showed revertant skin spots. Cas9-mediated enrichment of genomic DNA (gDNA) covering the two mutation sites (>8 kb) in COL7A1 and subsequent MinION sequencing successfully detected intragenic crossover in the epidermis of the clinically revertant skin. This method enables the discernment of haplotypes of up to a few tens of kilobases of gDNA. Moreover, it is devoid of polymerase chain reaction amplification, which can technically induce recombination. We, therefore, propose that nCATS is a powerful tool for understanding complicated gene modifications, including RM.
Assuntos
Epidermólise Bolhosa Distrófica , Sistemas CRISPR-Cas , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/diagnóstico , Epidermólise Bolhosa Distrófica/genética , Humanos , Mosaicismo , Mutação , PeleRESUMO
Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the role of spatiotemporal regulation of stem cells (SCs) has been implicated in this process, the mechanism underlying the development of such epidermal patterns is poorly understood. Here, we show that collagen XVII (COL17), a niche for epidermal SCs, helps stabilize epidermal patterns. Gene knockout and rescue experiments revealed that COL17 maintains the width of the murine tail scale epidermis independently of epidermal cell polarity. Skin regeneration after wounding was associated with slender scale epidermis, which was alleviated by overexpression of human COL17. COL17-negative skin in human junctional epidermolysis bullosa showed a distinct epidermal pattern from COL17-positive skin that resulted from revertant mosaicism. These results demonstrate that COL17 contributes to defining mouse tail scale shapes and human skin microtopography. Our study sheds light on the role of the SC niche in tissue pattern formation.
Assuntos
Autoantígenos , Epiderme , Colágenos não Fibrilares , Animais , Autoantígenos/genética , Epiderme/crescimento & desenvolvimento , Camundongos , Colágenos não Fibrilares/deficiência , Colágenos não Fibrilares/genética , Pele , Colágeno Tipo XVIIRESUMO
Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Polaridade Celular , Epiderme/metabolismo , Colágenos não Fibrilares/metabolismo , Proteína Quinase C/metabolismo , Animais , Autoantígenos/genética , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Colágenos não Fibrilares/genética , Isoformas de Proteínas/metabolismo , Colágeno Tipo XVIIRESUMO
We report 2 generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. Unlike the previous report in which IL-7 deficiency accompanied CD4 T lymphocytopenia, circulating CD4 T cells were not depleted in one of our patients, suggesting a GV pathogenesis other than poor T-cell development.
Assuntos
Linfócitos T CD4-Positivos , Interleucina-7/genética , Verrugas/genética , Alphapapillomavirus , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Verrugas/virologiaAssuntos
Campylobacter jejuni , Agamaglobulinemia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos , Celulite (Flegmão)/diagnóstico , Celulite (Flegmão)/tratamento farmacológico , Farmacorresistência Bacteriana , Fluoroquinolonas , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Macrolídeos/farmacologiaRESUMO
Growth and differentiation are reduced or stopped during hibernation, an energy conserving strategy in harsh seasons by lowered metabolism and body temperature. However, few studies evaluated this in a same individual using a non-invasive method. In this study, we applied a non-invasive tracking method of the nail growth throughout the hibernation period in the same hibernating animals, the Syrian hamster (Mesocricetus auratus). We found that nail growth was markedly suppressed during the hibernation period but rapidly recovered by the exit from the hibernation period. Our data suggest that nail growth was arrested during deep torpor, a hypometabolic and hypothermic state, but recovered during periodic arousal, a euthermic phase. Consistent with this, nail stem cells located in the nail matrix did not exit the cell cycle in the deep torpor. Thus, hibernation stops nail growth in a body temperature-dependent manner.
Assuntos
Hibernação , Animais , Hibernação/fisiologia , Mesocricetus , Unhas/fisiologia , Temperatura Corporal/fisiologia , Masculino , Cricetinae , Torpor/fisiologia , Temperatura BaixaAssuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias do Ceco/tratamento farmacológico , Hemangioma Capilar/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Cutâneas/induzido quimicamente , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biópsia , Substituição de Medicamentos , Feminino , Hemangioma Capilar/patologia , Hemangioma Capilar/cirurgia , Humanos , Pessoa de Meia-Idade , Panitumumabe , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento , RamucirumabRESUMO
Generalized verrucosis (GV) is a group of immunodeficiency disorders accompanied by widespread human papillomavirus infection. We revisit two cases of GV due to congenital interleukin-7 deficiency successfully treated with systemic retinoids. We also present a review of the literature on the use of systemic retinoids to treat GV. Our review suggests that systemic retinoids are a safe and effective option for managing recalcitrant wart lesions in cases of GV.
Assuntos
Síndromes de Imunodeficiência , Infecções por Papillomavirus , Verrugas , Humanos , Retinoides/uso terapêutico , Verrugas/tratamento farmacológico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/tratamento farmacológico , PapillomaviridaeAssuntos
Corticosteroides/administração & dosagem , Ciclosporina/administração & dosagem , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Dermatopatias Vesiculobolhosas/patologia , Administração Tópica , Criança , Humanos , Japão , Masculino , Prognóstico , Psoríase/patologia , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoAssuntos
Dermatite Atópica/diagnóstico , Dermatoses do Couro Cabeludo/diagnóstico , Pele/patologia , Administração Cutânea , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Glucocorticoides/administração & dosagem , Humanos , Masculino , Indução de Remissão , Couro Cabeludo , Dermatoses do Couro Cabeludo/tratamento farmacológico , Dermatoses do Couro Cabeludo/patologia , Pele/efeitos dos fármacos , Resultado do Tratamento , Adulto JovemRESUMO
Hemidesmosomes (HDs) are adhesion complexes that promote epithelial-stromal attachment in stratified and complex epithelia, including the epidermis. In various biological processes, such as differentiation and migration of epidermal keratinocytes during wound healing or carcinoma invasion, quick assembly and disassembly of HDs are prerequisites. In this study, we show that inhibition of Wnt/ß-catenin signaling disturbs HD organization in keratinocytes. Screening with inhibitors identified the depletion of HD components and HD-like structures through Wnt inhibition, but keratinocyte differentiation was not affected. Wnt inhibition significantly diminished plectin and type XVII collagen expression in the basal side of Wnt-inhibited cells and the dermo-epidermal junction of the Wnt-inactive murine basal epidermis. Similar to Wnt inhibition, PLEC-knockout cells or cells with plectin-type XVII collagen binding defects showed type XVII collagen reduction in the basal side of the cells, implying the possible involvement of Wnt/ß-catenin signaling in HD assembly. Atypical protein kinase C inhibition ameliorated the phenotypes of Wnt-inhibited cells. These findings show that Wnt/ß-catenin signaling regulates the localization of HD components in keratinocytes and that the atypical protein kinase C pathway is involved in Wnt inhibitionâinduced HD disarrangement. Our study suggests that the Wnt signaling pathway could be a potential therapeutic target for treating HD-defective diseases, such as epidermolysis bullosa.
Assuntos
Hemidesmossomos , beta Catenina , Animais , Hemidesmossomos/metabolismo , Queratinócitos/metabolismo , Camundongos , Plectina , Via de Sinalização Wnt , Cicatrização/fisiologia , beta Catenina/metabolismoRESUMO
The skin barrier is provided by the organized multi-layer structure of epidermal cells, which is dynamically maintained by a continuous supply of cells from the basal layer. The epidermal homeostasis can be disrupted by various skin diseases, which often cause morphological changes not only in the epidermis but in the dermis. We present a three-dimensional agent-based computational model of the epidermis that takes into account the deformability of the dermis. Our model can produce a stable epidermal structure with well-organized layers. We show that its stability depends on the cell supply rate from the basal layer. Modeling the morphological change of the dermis also enables us to investigate how the stiffness of the dermis affects the structure and barrier functions of the epidermis. Besides, we show that our model can simulate the formation of a corn (clavus) by assuming hyperproliferation and rapid differentiation. We also provide experimental data for human corn, which supports the model assumptions and the simulation result.