RESUMO
The hair follicle and nail unit develop and regenerate through epithelial-mesenchymal interactions. Here, we review some of the key signals and molecular interactions that regulate mammalian hair follicle and nail formation during embryonic development and how these interactions are reutilized to promote their regeneration during adult homeostasis and in response to skin wounding. Finally, we highlight the role of some of these signals in mediating human hair follicle and nail conditions.
Assuntos
Folículo Piloso , Unhas , Folículo Piloso/embriologia , Humanos , Unhas/embriologia , Unhas/crescimento & desenvolvimento , Animais , Transdução de Sinais , Regeneração/fisiologiaRESUMO
Vertebrate Hox genes are critical for the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here, we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that the HoxC gene cluster was co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws. Accordingly, deletion of the HoxC cluster led to mice lacking nails (anonychia), a condition stronger than the previously reported loss of function of Hoxc13, which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two mammalian-specific ectodermal enhancers located upstream of the HoxC gene cluster, which together regulate Hoxc gene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation of Hoxc genes in the ectoderm, suggesting that these two enhancers may have evolved along with the mammalian taxon to provide the level of HOXC proteins necessary for the full development of hair and nail.
Assuntos
Ectoderma/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Folículo Piloso/metabolismo , Unhas/metabolismo , Animais , Biomarcadores , Ectoderma/embriologia , Folículo Piloso/embriologia , Humanos , Camundongos , Camundongos Knockout , Unhas/embriologiaRESUMO
PURPOSE: Our group had recently described human hand Pacinian corpuscles (PCs): the hand PCs are not simply arranged along the digital palmar nerves but often exhibited specific morphologies known uncommonly. However, there is still no or few information about human foot PCs. MATERIALS AND METHODS: We observed transverse sections of all five toes including the interdigital area obtained from 12 feet of eight fetuses at 28-33 weeks (crown-rump length 230-290mm). Serial sections were prepared for 3D reconstructions and measurement. RESULTS: Foot PCs were characterized by (1) a dense distribution in the interdigital area in contrast to a few PCs in the distal tip of the all five toes; (2) abundant dorsal PCs including those in the nail bed and: (3) a long chain of PCs in the flexor tendon sheath of all five toes. Therefore, a distal dominance was not evident in the foot in contrast to the hand and, a tendon sheath contained much greater numbers of PCs than the hand. A tree-like or bouquet-like arrangement of PCs along a short perforating artery to the palmar digital skin was seen in the foot as we had described in the hand. The tree of foot PCs was sometimes seen laying transversely along the digital skin surface, not toward the skin. CONCLUSION: It is still unknown that, in utero, how the PCs distribution became different between the hand and foot: it might be determined genetically in a region-specific manner.
Assuntos
Feto/anatomia & histologia , Pé/embriologia , Corpúsculos de Pacini/embriologia , Feminino , Humanos , Imageamento Tridimensional , Imuno-Histoquímica , Masculino , Unhas/embriologia , Corpúsculos de Pacini/anatomia & histologia , Corpúsculos de Pacini/química , Tendões/embriologia , Dedos do Pé/embriologiaRESUMO
Our knowledge on stem cells of the hair follicle has increased exponentially after the bulge was characterized as the stem cell niche two decades ago. In contrast, little is known about stem cells in the nail unit. Whereas hair follicles are plentiful and easy to access, the human body has only twenty nails and they are rarely biopsied. Therefore, examining fetal material offers unique advantages. In the following mini-review, our current knowledge on nail stem cells is summarized and analogies to the hair follicle stem cells are drawn.
Assuntos
Células-Tronco Embrionárias/citologia , Unhas/citologia , Unhas/embriologia , HumanosRESUMO
BACKGROUND: Recently, an intriguing concept was introduced into the literature that defines the area underlying the nail bed as a specific mesenchymal substructure unique to the nail organ. It has been termed onychodermis. The onychodermis expresses CD10 with remarkable specificity. Herein, we compare adult and fetal human hair follicles with fetal nail organs in an attempt to draw analogies for the mesenchyme associated with both adnexal structures. METHODS: We examined immunohistochemically samples from adult and fetal hair follicles for the expression of CD10, CD34 and the mesenchymal stem cell marker nestin and compared the antigen profile with that of the fetal nail organ. RESULTS: The CD10-positive/CD34-negative onychodermis is prominently visible at the end of the second trimester. A corresponding follicular structure was not identified, either in the adult or in the developing hair follicle. Nestin staining does not define the onychodermis. CONCLUSIONS: The concept of the onychodermis is equally valid in the developing nail organ where it is also defined by its expression for CD10. Its function may be related to the anchorage of the overlying nail bed but may also involve a more dynamic role in the induction of hard keratins in the latter, contributing to the formation of the nail plate.
Assuntos
Folículo Piloso/embriologia , Mesoderma/embriologia , Unhas/embriologia , Adulto , Fatores Etários , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Feminino , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Unhas/citologia , Unhas/metabolismo , Neprilisina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina , Gravidez , Segundo Trimestre da GravidezRESUMO
BACKGROUND: Although the bulge is well characterized as a stem cell niche of the hair follicle, comparatively little is known about the location of stem cells in the nail. Herein, we describe the spatiotemporal expression pattern of six stem cell markers in the developing human nail and compared it with the embryonic and fetal human hair follicle. The areas of proliferative activity were additionally examined using labeling with Ki-67. METHODS: We examined immunohistochemically samples from embryonic and fetal human nail, hair and skin for the expression of cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK19), PHLDA1, CD200, nestin and Ki-67 using standard techniques. RESULTS: CK15 (clone LHK15), CK19 and PHLDA1 are negative in the nail and hair matrix but positive in the ventral proximal nail fold and in the follicular bulge. Over the course of embryogenesis they display a highly specific spatiotemporal expression pattern both in the nail and in the hair follicle. CONCLUSIONS: We propose that at least during embryogenesis the proximal ventral nail fold represents the niche for the nail stem cells. In contrast to animal experiments, autoradiographic pulse-chasing studies cannot be performed in human, and immunohistochemical studies are a valid alternative although they have their limitations. Further studies on adult human nail units are suggested.
Assuntos
Antígenos de Diferenciação/biossíntese , Unhas/embriologia , Pele/embriologia , Nicho de Células-Tronco/fisiologia , Células-Tronco/metabolismo , Adulto , Antígenos CD/biossíntese , Feminino , Humanos , Proteínas de Filamentos Intermediários/biossíntese , Queratina-15/biossíntese , Queratina-19/biossíntese , Antígeno Ki-67/biossíntese , Masculino , Unhas/citologia , Proteínas do Tecido Nervoso/biossíntese , Nestina , Pele/citologia , Células-Tronco/citologia , Fatores de Transcrição/biossínteseRESUMO
Hereditary leukonychia (porcelain nails or white nails) is a rare nail disorder with an unknown genetic basis. To identify variants in a gene underlying this phenotype, we identified four families of Pakistani origin showing features of hereditary leukonychia. All 20 nails of each affected individual were chalky and white in appearance, consistent with total leukonychia, with no other cutaneous, appendageal, or systemic findings. By using Affymetrix 10K chip, we established linkage to chromosome 3p21.3-p22 with a LOD score (Z) of 5.1. We identified pathogenic mutations in PLCD1 in all four families, which encodes phosphoinositide-specific phospholipase C delta 1 subunit, a key enzyme in phosphoinositide metabolism. We then identified localization of PLCD1 in the nail matrix. It was recently shown that PLCD1 is a component of the human nail plate by proteomic analysis and is localized in the matrix of human nails. Furthermore, mutations detected in PLCD1 resulted in reduced enzymatic activity in vitro. Our data show that mutations in PLCD1 underlie hereditary leukonychia, revealing a gene involved in molecular control of nail growth.
Assuntos
Cromossomos Humanos Par 3/genética , Unhas/patologia , Fosfolipase C delta/genética , Humanos , Hipopigmentação/enzimologia , Hipopigmentação/genética , Hipopigmentação/patologia , Mutação , Doenças da Unha/congênito , Doenças da Unha/enzimologia , Doenças da Unha/genética , Doenças da Unha/patologia , Unhas/embriologia , Unhas/enzimologia , Linhagem , Fosfolipase C delta/metabolismoRESUMO
BACKGROUND: The sex-determining gene Sox9 was recently unexpectedly found to have an essential role in outer root sheath differentiation. It was also characterized as a general marker of basal cell carcinoma. Herein, we describe its spatiotemporal expression pattern outside the hair follicle during human cutaneous embryogenesis. METHODS: We examined immunohistochemically samples from embryonic and fetal human skin for the expression of SOX9 using standard techniques. For comparison reasons, we also included scalp skin from adults. RESULTS: SOX9 is expressed in the developing nail organ, eccrine glands, blood vessels and melanocytes/melanoblasts. In the nail organ, the nail bed but not the nail matrix was immunoreactive for SOX9. In plantar skin, SOX9 specifically labels the evolving eccrine glands but not the interfollicular keratinocytes. CONCLUSIONS: The distinctive expression pattern of SOX9 during human cutaneous embryogenesis indicates a key role in skin homeostasis that includes but goes beyond its role in outer root sheath differentiation. Studying immunohistochemical markers in developing human skin has the potential to further our understanding of adult skin physiology and to deepen our concepts especially of the histogenesis of adnexal tumors (including those of the nail unit) and the relationship of the various adnexal structures to each other.
Assuntos
Folículo Piloso/embriologia , Unhas/embriologia , Fatores de Transcrição SOX9/metabolismo , Pele/embriologia , Adulto , Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento , Folículo Piloso/metabolismo , Humanos , Imuno-Histoquímica , Unhas/metabolismo , Pele/metabolismoRESUMO
BACKGROUND: The role of stem cells in maintaining the sebaceous gland throughout the various stages of life is not satisfactorily resolved. In a recent article, the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) was proposed as a marker of a population of unipotent progenitor cells that reside in the sebaceous gland, regulating its size and activity. METHODS: We used standard immunohistochemical methods to examine Blimp-1 expression in samples from embryonic, fetal and adult human skin and in 119 sebaceous lesions comprising all major categories of sebocytic lineage, including hamartomas, cysts and benign and malignant neoplasms. RESULTS: Blimp-1 is expressed late in embryonic development and is restricted to the evolving sebaceous gland, the terminally differentiating components of the hair follicle and nail organ and the granular layer. This pattern is preserved into adult life. In all sebaceous lesions, Blimp-1 labels only the most mature cellular constituents. CONCLUSIONS: The reported expression pattern is difficult to reconcile with a function of Blimp-1 as a marker for sebocytic progenitor cells but indicates a major role in terminal differentiation. Within the interfollicular epidermis, its exclusive localization to the granular layer suggests a central function in skin barrier homeostasis in the human.
Assuntos
Diferenciação Celular/fisiologia , Proteínas Repressoras/metabolismo , Glândulas Sebáceas/metabolismo , Células-Tronco/metabolismo , Linhagem da Célula/fisiologia , Folículo Piloso/embriologia , Folículo Piloso/metabolismo , Humanos , Imuno-Histoquímica , Unhas/embriologia , Unhas/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Glândulas Sebáceas/embriologiaRESUMO
To examine the X-inactivation patterns of normal human nails, we performed the human androgen receptor gene assay of DNA samples extracted separately from each finger and toe nail plates of nine female volunteers. The X-inactivation pattern of each nail was unique and constant for at least 2 years. The frequency of nails with one of the two X-chromosomes exclusively inactivated was 25.9%. In the nails composed of two types of cells with either one X-chromosome inactivated, the two cell types were distributed in patchy mosaics. These findings suggest that the composition of precursor cells of each nail is maintained at each site at least through several cycles of regeneration time, and that the nail plate has a longitudinal band pattern, each band consisting of cells with only one of the two X-chromosomes inactivated. Using the frequency of nails with one of two X-chromosomes exclusively inactivated, we estimated the number of progenitor cells that gave rise to the nail plate during development to be about 3, under the assumption that the process follows the binominal distribution model. A strong correlation observed among the big, index and little fingers, and among the corresponding toes suggests an interesting interpretation concerning their morphogenetic process.
Assuntos
Unhas/metabolismo , Inativação do Cromossomo X , Feminino , Humanos , Masculino , Unhas/citologia , Unhas/embriologia , Receptores Androgênicos/genética , Células-TroncoRESUMO
BACKGROUND: Basal cell carcinoma (BCC) is still viewed by many dermatologists as a tumor of the interfollicular epidermis, although references were made early in the dermatopathologic literature to the resemblance of BCC to the hair follicle. OBJECTIVE: Our aim was to characterize the common expression pattern for the epithelial cell adhesion molecule (Ep-CAM) in BCCs, various stages of follicular embryogenesis, and adult hair follicles and, thereby, in analogy point to the similarity between BCC and the hair follicle. METHODS: We studied immunohistochemically 16 superficial BCCs for Ep-CAM and compared the expression pattern with that during hair follicle, nail, and eccrine gland development in human embryos and fetuses. In addition, we examined terminal scalp and vellus hair follicles. RESULTS: All BCCs expressed Ep-CAM similar to the early stages of the embryonic human hair follicle, the secondary hair germ, and the outer root sheath of the vellus hair follicle. The embryonic nail organ and the adult anagen hair follicles were completely negative. LIMITATIONS: The conclusions are based on the similarity in the immunohistochemical expression profile for a single adhesion molecule. CONCLUSION: BCC expresses the cell-cell adhesion molecule Ep-CAM similar to the embryonic hair germ, the secondary hair germ of the terminal hair follicle, and the outer root sheath of the vellus hair follicle. We suggest that this may be a clue to the adnexal nature of BCC and propose that BCC is the most primitive follicular tumor.
Assuntos
Antígenos de Neoplasias/metabolismo , Carcinoma Basocelular/metabolismo , Moléculas de Adesão Celular/metabolismo , Folículo Piloso/embriologia , Folículo Piloso/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Glândulas Écrinas/embriologia , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário , Molécula de Adesão da Célula Epitelial , Humanos , Imuno-Histoquímica , Unhas/embriologia , Couro CabeludoRESUMO
Psoriasis is a chronic skin disease that affects millions of people throughout the world. Even though cutaneous signs and symptoms are the most common clinical manifestations, the nails can be involved in up to 50% of cases, and their involvement remains an important yet often overlooked aspect of the disease. There is a broad spectrum of nail dystrophies associated with psoriasis, ranging from the common pitting and loosening of the nail plate to the less frequent discoloration and splinter hemorrhages seen in the nail bed. This article discusses the normal anatomy and embryology of the nail unit as well as the current understanding of the pathogenesis of the disease. It also provides an extensive review of the existing literature with respect to psoriatic nail therapy. Although there have been many recent advances in the treatment of the cutaneous form of the disease-most notably in the field of immunotherapies-the options for nail psoriasis are far more limited. While a number of treatment alternatives currently exist for nail disease, the general paucity of clear evidence regarding these choices often makes it difficult to select the most efficient, safe, and optimal treatment for the patient. Even though the current literature has shown some support for the use of topical, intralesional, radiation, systemic, and combination therapies for nail psoriasis, the available studies lack sufficient power to extrapolate a standardized therapeutic regimen. Therefore, until better-documented evidence validating the treatment options emerges within the literature, clinicians and patients are left with a vague and relatively unproven approach to psoriatic nail disease.
Assuntos
Doenças da Unha , Unhas/anatomia & histologia , Psoríase , Administração Tópica , Corticosteroides/administração & dosagem , Antralina/uso terapêutico , Ensaios Clínicos como Assunto , Ciclosporina/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Injeções Intralesionais , Doenças da Unha/diagnóstico , Doenças da Unha/patologia , Doenças da Unha/radioterapia , Doenças da Unha/terapia , Unhas/embriologia , Unhas/fisiologia , Ácidos Nicotínicos/uso terapêutico , Fotoquimioterapia , Fototerapia , Psoríase/diagnóstico , Psoríase/imunologia , Psoríase/patologia , Psoríase/radioterapia , Psoríase/terapiaRESUMO
The R-spondins are a relatively recently identified family of secreted proteins linked to the Wnt signaling pathway. Recently, human phenotypes have been associated with mutations in two human R-spondins. Germline RSPO4 and RSPO1 mutations result in recessive anonychia (absence of all fingernails and toenails) and a recessive syndrome with XX-male sex reversal, PPK and a predisposition to SCC, respectively. This review discusses the key roles R-spondins play in embryogenesis, adult tissue maintenance and skin carcinogenesis.
Assuntos
Carcinoma/genética , Unhas/embriologia , Neoplasias Cutâneas/genética , Trombospondinas/fisiologia , Disgenesia Gonadal/genética , Humanos , Doenças da Unha/genética , Trombospondinas/genéticaRESUMO
Hair and nail development have many similarities and are likely to share many developmental pathways. This is evident from the ectodermal dysplasias that affect both appendages. Of special interest are syndromic disorders as they show the effects of disturbances in molecular pathways that are essential for normal embryonic development. In this review, recent results from studies of syndrome affecting hair and nail development will be discussed.
Assuntos
Doenças do Cabelo/genética , Doenças do Cabelo/patologia , Doenças da Unha/genética , Doenças da Unha/patologia , Adesão Celular/fisiologia , Citoesqueleto/fisiologia , Desmossomos/fisiologia , Regulação da Expressão Gênica , Folículo Piloso/embriologia , Folículo Piloso/fisiopatologia , Humanos , Unhas/embriologia , Unhas/fisiopatologia , SíndromeRESUMO
This article provides a description of the growth and anatomic structure of the human nails.
Assuntos
Unhas/anatomia & histologia , Humanos , Microscopia Eletrônica de Varredura , Unhas/embriologia , Unhas/ultraestruturaRESUMO
The nail is a unique structure in the human. Its anatomy and physiology are not well understood by many physicians caring for nail problems. The perionychial anatomy is described along with the physiology pertinent to care of the nail and its surroundings.
Assuntos
Doenças da Unha/patologia , Unhas/anatomia & histologia , Unhas/fisiologia , Humanos , Unhas/embriologia , Unhas/inervaçãoRESUMO
Nail changes may be marker lesions for complex systemic disorders and herald associated syndromes. Knowledge of the anatomy, embryology and biochemical properties of the nail apparatus is essential for understanding the pathogenesis of hereditary nail disorders. In the last few years significant progress has been made in the field of clinical and molecular pathology of human diseases. A considerable number of the genes responsible for genodermatoses have been identified. The homeobox master control genes, genes encoding for transcription factors, genes encoding for the maintenance of telomeres, or for structural molecules, such as the similarly evolutionary highly conserved a-helical rod domains of keratins, are involved in the embryogenesis and normal functioning of nails. Using nail changes in selected genodermatoses with a known genetic background, we try to elucidate the genesis of inherited nail disorders and review the resultant clinical manifestations.
Assuntos
Anormalidades Múltiplas , Doenças da Unha , Unhas/anatomia & histologia , Dermatopatias Genéticas , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Disceratose Congênita/embriologia , Disceratose Congênita/genética , Humanos , Doenças da Unha/congênito , Doenças da Unha/genética , Doenças da Unha/patologia , Síndrome da Unha-Patela/embriologia , Síndrome da Unha-Patela/genética , Unhas/embriologia , Unhas/fisiologia , Síndrome de Rubinstein-Taybi/embriologia , Síndrome de Rubinstein-Taybi/genética , Dermatopatias Genéticas/patologiaRESUMO
Paleontological evidence indicates that the evolutionary diversification of mammals early in the Cenozoic era was characterized by an adaptive radiation of distal limb structures. Likewise, neontological data show that morphological variation in distal limb integumentary appendages (e.g., nails, hooves, and claws) can be observed not only among distantly related mammalian taxa but also among closely related species within the same clade. Comparative analysis of nail, claw, and hoof morphogenesis reveals relatively subtle differences in mesenchymal and epithelial patterning underlying these adult differences in distal limb appendage morphology. Furthermore, studies of regulatory gene expression during vertebrate claw development demonstrate that many of the signaling molecules involved in patterning ectodermal derivatives such as teeth, hair, and feathers are also involved in organizing mammalian distal limb appendages. For example, Bmp4 signaling plays an important role during the recruitment of mesenchymal cells into the condensations forming the terminal phalanges, whereas Msx2 affects the length of nails and claws by suppressing proliferation of germinal epidermal cells. Evolutionary changes in the form of distal integumentary appendages may therefore result from changes in gene expression during formation of mesenchymal condensations (Bmp4, posterior Hox genes), induction of the claw fold and germinal matrix (shh), and/or proliferation of epidermal cells in the claw matrix (Msx1, Msx2). The prevalence of convergences and parallelisms in nail and claw structure among mammals underscores the existence of multiple morphogenetic pathways for evolutionary change in distal limb appendages.