RESUMO
Primary cicatricial alopecias (PCAs) are a group of skin diseases in which there is progressive and permanent destruction of hair follicles followed by replacement with fibrous tissue. Unfortunately, by the time patients seek clinical evaluation of their hair loss, the skin is already inflamed and/or scarred, so there is little hope for a return to their normal hair growth pattern. Clinical and basic science investigations are now focusing on three forms of human PCA: lichen planopilaris (LPP), frontal fibrosing alopecia (FFA) and central centrifugal cicatricial alopecia (CCCA). Transcriptome, lipidome and other new technologies are providing new insight into the pathogenesis of some of these diseases that are being validated and further investigated using spontaneous and genetically engineered mouse models.
Assuntos
Alopecia/diagnóstico , Alopecia/etiologia , Cicatriz/diagnóstico , Cicatriz/etiologia , Modelos Animais de Doenças , Líquen Plano/diagnóstico , Pele/patologia , Alopecia/patologia , Alopecia/terapia , Animais , Cicatriz/patologia , Cicatriz/terapia , Cães , Fibrose , Humanos , Líquen Plano/patologia , Camundongos , Couro CabeludoRESUMO
Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant hair disorder. Through the study of a mouse model, we identified a mutation in the 5'-untranslated region of the hairless (HR) gene in patients with MUHH in a Caucasian family. The corresponding mutation, named 'hairpoor', was found in mutant mice that were generated through N-ethyl-N-nitrosourea mutagenesis. Hairpoor mouse mutants display partial hair loss at an early age and progress to near alopecia, which resembles the MUHH phenotype. This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway. This study indicates that the gain in function of HR also results in alopecia, as seen with the loss of function of HR, via abnormal upregulation of the Wnt signaling pathway.
Assuntos
Expressão Gênica , Hipotricose/congênito , Hipotricose/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Proteínas Wnt/metabolismo , Regiões 5' não Traduzidas , Animais , Sequência de Bases , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Hipotricose/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mutação , Linhagem , Fatores de Transcrição/metabolismo , Regulação para Cima , Proteínas Wnt/genéticaRESUMO
The hair follicle is considered to be a model system for studying organogenesis. In our initial study using mouse cells (Zheng et al., 2005) we found that new hair follicle formation always starts from an epithelial platform: the epidermal cells aggregate, the aggregates encyst, and from the periphery of the cysts, centrifugally, hair buds, pegs, and follicles form. In this report, we extend our initial study to four distantly related mammals: opossum, rat, dog and human. We find that in these four species, plus mouse, the most trichogenic cells are found in the earliest stages of hair follicle development and that the cellular mechanism of new hair follicle formation starting from dissociated cells is largely the same. These studies suggest that there is essentially one way by which dissociated mammalian skin cells form a new hair follicle in vivo and that this mechanism has been highly conserved.
Assuntos
Folículo Piloso/embriologia , Organogênese/fisiologia , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Cães , Folículo Piloso/citologia , Humanos , Gambás , Organogênese/genética , Ratos , Pele/citologia , Pele/metabolismoRESUMO
Hair follicle morphogenesis and regeneration occur by an extensive and collaborative crosstalk between epithelial and mesenchymal skin components. A series of pioneering studies, which revealed an indispensable role of follicular dermal papilla and dermal sheath cells in this crosstalk, has led workers in the field to study in detail the anatomical distribution, functional properties, and molecular signature of the trichogenic dermal cells. The purpose of this paper was to provide a practical summary of the development and recent advances in the study of trichogenic dermal cells. Following a short review of the relevant literature, the methods for isolating and culturing these cells are summarized. Next, the bioassays, both in vivo and in vitro, that enable the evaluation of trichogenic properties of tested dermal cells are described in detail. A list of trichogenic molecular markers identified by those assays is also provided. Finally, this methods review is completed by defining some of the major questions needing resolution.
Assuntos
Técnicas de Cultura de Células , Folículo Piloso/citologia , Folículo Piloso/crescimento & desenvolvimento , Morfogênese , Regeneração , Animais , Biomarcadores/metabolismo , Separação Celular , Folículo Piloso/metabolismo , Humanos , Mesoderma/fisiologiaRESUMO
Recent advances in epithelial stem cell biology have resulted in the isolation of hair follicle stem cells, which generate hair follicles when injected into immunodeficient mice. These isolated hair follicle epithelial stem cells must be combined with 'inductive' dermal cells to produce new hair follicles. The advent of techniques for cultivating inductive dermal cells and competent epithelial stem cells creates the opportunity to bioengineer hair follicles for the treatment of hair loss.
Assuntos
Folículo Piloso/citologia , Engenharia Tecidual/métodos , Técnicas de Cultura de Células/métodos , Células Epiteliais/citologia , Folículo Piloso/embriologia , Folículo Piloso/crescimento & desenvolvimento , Humanos , Mesoderma/citologia , Modelos Biológicos , Medicina Regenerativa/métodos , Pele/citologia , Células-Tronco/citologiaRESUMO
Androgenetic alopecia In men, or male pattern baldness, is recognized increasingly as a physically and psychologically harmful medical condition that can be managed effectively by generalist clinicians. This article discusses the clinical manifestations, epidemiology, physical and psychosocial importance, pathophysiology, diagnosis, and management of androgenetic alopecia in men. Androgenetic alopecia affects at least half of white men by the age of 50 years. Although androgenetic alopecia does not appear to cause direct physical harm, hair loss can result in physical harm because hair protects against sunburn, cold, mechanical injury, and ultraviolet light. Hair loss also can psychologically affect the balding individual and can Influence others' perceptions of him. A progressive condition, male pattern baldness is known to depend on the presence of the androgen dihydrotestosterone and on a genetic predisposition for this condition, but its pathophysiology has not been elucidated fully. Pharmacotherapy, hair transplantation, and cosmetic aids have been used to manage male pattern baldness. Two US Food and Drug Administration-approved hair-loss pharmacotherapies-the potassium channel opener minoxidil and the dihydrotestosterone synthesis inhibitor finasteride--are safe and effective for controlling male pattern baldness with long-term daily use. Regardless of which treatment modality is chosen for male pattern baldness, defining and addressing the patient's expectations regarding therapy are paramount in determining outcome.
Assuntos
Alopecia/terapia , Alopecia/diagnóstico , Alopecia/fisiopatologia , Alopecia/psicologia , Finasterida/uso terapêutico , Cabelo , Humanos , Masculino , Minoxidil/uso terapêuticoRESUMO
BACKGROUND: Primary cicatricial alopecias encompass a group of disorders characterized by permanent destruction of the hair follicle. The varied clinical features and differences in terminology have led to difficulties in defining consistent clinicopathologic correlation. OBJECTIVE: We sought clinicopathologic correlation of 6 clinically distinct primary cicatricial alopecias: lichen planopilaris, frontal fibrosing alopecia, pseudopelade (Brocq), central centrifugal alopecia, folliculitis decalvans, and tufted folliculitis. METHODS: We conducted prospective and blinded histopathologic evaluation of clinically typical primary cicatricial alopecias. Biopsy specimens were taken from early affected scalp lesions and paired with samples from clinically unaffected areas in the same patient. RESULTS: The lymphocytic and neutrophilic groups were readily distinguished histologically. However, within the two groups clinically distinct primary cicatricial alopecias could not be distinguished with current histopathologic techniques. CONCLUSION: A descriptive, standardized histopathologic reporting of follicular architecture, type, location, and extent of the inflammatory infiltrate, and presence or absence of sebaceous glands, may be of greatest value in guiding the treatment of patients with primary cicatricial alopecias.
Assuntos
Alopecia/patologia , Adulto , Idoso , Alopecia/classificação , Cicatriz/classificação , Cicatriz/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Delta-6 desaturase, also known as fatty acid desaturase-2 (FADS2), is a component of a lipid metabolic pathway that converts the essential fatty acids linoleate and alpha-linolenate into long-chain polyunsaturated fatty acids. Isolation of Delta-6 desaturase/FADS2 cDNA from human skin predicts an identical protein to that expressed in human brain and Southern analysis indicates a single locus, together suggestive of a single Delta-6 desaturase/FADS2 gene. Within human skin, Delta-6 desaturase/FADS2 mRNA and protein expression is restricted to differentiating sebocytes located in the suprabasal layers of the sebaceous gland. Enzymatic analysis using CHO cells overexpressing human Delta-6 desaturase/FADS2 indicates catalysis of a "polyunsaturated fatty acid type" reaction, but also an unexpected "sebaceous-type" reaction, that of converting palmitate into the mono-unsaturated fatty acid sapienate, a 16-carbon fatty acid with a single cis double bond at the sixth carbon from the carboxyl end. Sapienate is the most abundant fatty acid in human sebum, and among hair-bearing animals is restricted to humans. This work identifies Delta-6 desaturase/FADS2 as the major fatty acid desaturase in human sebaceous glands and suggests that the environment of the sebaceous gland permits catalysis of the sebaceous-type reaction and restricts catalysis of the polyunsaturated fatty acid type reaction.
Assuntos
Ácidos Graxos Dessaturases/química , Glândulas Sebáceas/enzimologia , Animais , Northern Blotting , Southern Blotting , Encéfalo/metabolismo , Células CHO , Clonagem Molecular , Cricetinae , DNA Complementar/metabolismo , Ácidos Graxos Dessaturases/biossíntese , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Insaturados/metabolismo , Vetores Genéticos , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linoleoil-CoA Desaturase , Metabolismo dos Lipídeos , Modelos Químicos , Fases de Leitura Aberta , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Sebo/metabolismo , Análise de Sequência de DNA , Pele/metabolismo , Distribuição TecidualRESUMO
The hair growth cycle is generally recognized to comprise phases of growth (anagen), regression (catagen), and rest (telogen). Whereas, heretofore, the hair shedding function has been assumed to be part of the telogen phase, using a laboratory mouse model and newly developed techniques for quantitative collection and spectroscopic determination of shed hair, we found that shedding actually occurs as a distinct phase. Although some shedding occurs throughout the growth cycle, the largest peak is coupled to anagen. Using hair dye and rhodamine labeling we established that the shafts that shed arise during the previous hair cycle. We found that over the cycle the ratio of shed overfur to shed underfur hair shafts varies with the cycle phase and that the shed shaft base is unique morphologically, having a cylindrical shape with scalloped or "nibbled" edges. By electron microscopy the mooring cells of the exogen root show intercellular separation suggesting a proteolytic process in the final shedding step. This is the first report describing a distinct shedding, or exogen, phase of the hair cycle. This study supports the notion that this phase is uniquely controlled and that the final step in the shedding process involves a specific proteolytic step.
Assuntos
Cabelo/fisiologia , Cabelo/ultraestrutura , Muda/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Modelos Animais , Gravidez , Curetagem a Vácuo/instrumentaçãoRESUMO
The goal of regenerative medicine is to reconstruct fully functional organs from tissue culture expanded human cells. In this study, we report a method for human reconstructed skin (hRSK) when starting with human cells. We implanted tissue culture expanded human epidermal and dermal cells into an excision wound on the back of immunodeficient mice. Pigmented skin covered the wound 4 weeks after implantation. Hair shafts were visible at 12 weeks and prominent at 14 weeks. Histologically, the hRSK comprises an intact epidermis and dermis with mature hair follicles, sebaceous glands and most notably, and unique to this system, subcutis. Morphogenesis, differentiation, and maturation of the hRSK mirror the human fetal process. Human antigen markers demonstrate that the constituent cells are of human origin for at least 6 months. The degree of new skin formation is most complete when using tissue culture expanded cells from fetal skin, but it also occurs with expanded newborn and adult cells; however, no appendages formed when we grafted both adult dermal and epidermal cells. The hRSK system promises to be valuable as a laboratory model for studying biological, pathological, and pharmaceutical problems of human skin.
Assuntos
Folículo Piloso/citologia , Pele/citologia , Animais , Derme/citologia , Células Epidérmicas , Humanos , Masculino , Camundongos , Engenharia TecidualRESUMO
Little attention has been given to the impact of lipid metabolism on hair follicle biology and pathology. Three recent papers (one in the current issue) describe a major effect of altered lipid metabolism on hair growth. A direct link was made to at least one form of cicatricial alopecia, but the role lipids play in other follicular pathologies, such as the acneiform conditions, are inadequately explored and must be tested.
Assuntos
Acne Vulgar/metabolismo , Alopecia/metabolismo , Cabelo/metabolismo , Metabolismo dos Lipídeos/fisiologia , Equilíbrio Hidroeletrolítico/fisiologia , Acne Vulgar/patologia , Alopecia/patologia , Animais , Cabelo/crescimento & desenvolvimento , Homeostase/fisiologia , HumanosRESUMO
One challenge faced by stem cell biologists is the bioengineering of an organ. Ehama et al. (2007, this issue) used cells derived from human and rodent epidermis and dermal papilla to reconstitute hair-follicle mini-organs. Some result in hair follicles; others are hair follicle-like. The challenge calls for the development of a set of criteria to define a hair follicle so that bioengineered products in the future can be evaluated.
Assuntos
Engenharia Biomédica/métodos , Folículo Piloso/citologia , Células-Tronco/citologia , Animais , Desenvolvimento Embrionário , Epiderme , Humanos , Camundongos , Modelos Biológicos , Técnicas de Cultura de Órgãos/métodosRESUMO
Plucked (pk) is an autosomal recessive mouse mutation with a hair phenotype that arose spontaneously in the DBA/2J strain. Histological studies indicate that adult pk mutant mice lose truncal hair because of the scarring of follicles due to an apparent obstruction of the outward movement of the hair shaft within the follicular canal. We mapped the pk mutant phenotype to a 1.1cM region of chromosome 18 (between 6.6 and 7.7 cM from the centromere) using 370 backcross progeny. Within this region, among others, are genes for desmosome cadherins. Desmosome cadherins are interesting candidates because of their critical roles for cell-cell adhesion in epidermal function. Northern Blot analysis of wild-type and pk mutant mice indicates that expression of both desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) is up-regulated in the skin of mutant pk mice.
Assuntos
Caderinas/genética , Proteínas do Citoesqueleto/genética , Mutação/genética , Regulação para Cima/genética , Animais , Mapeamento Cromossômico , Desmogleína 1 , Desmogleína 3 , Desmogleínas , Desmoplaquinas , Feminino , Folículo Piloso/citologia , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Humanos , Masculino , Camundongos , Camundongos Mutantes , Morfogênese , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/metabolismoRESUMO
BACKGROUND: An animal model for the study of basal cell carcinoma (BCC) is required to better understand its biology. Several attempts to grow BCC in immuno-incompetent animals have been only modestly successful. METHODS: To test the ability of BCC to grow in a mouse with complete and severe immuno-incompetence, 14 individual BCC were transplanted into the subcutaneous tissue of 18 SCID-beige mice (T, B and natural killer cell deficient). Light microscopy and immunophenotypic analyses were performed on primary BCC and first and seventh passage tumors. RESULTS: Transplantation of three BCC yielded rapidly growing anaplastic tumors for a tumor take of 18% (3/18). SCID-beige mice without tumor growth had mostly scars or epidermoid cysts at the transplant sites. The three patients whose BCC gave rise to the anaplastic tumors were significantly older than those without tumor growth (87 vs. 64, p = 0.001), but they did not differ with respect to BCC type or general health. These three anaplastic tumors were histologically and immunophenotypically similar, being composed of dyscohesive, pleomorphic cells that expressed vimentin and smooth muscle actin. In the first passage mice these tumors were locally invasive, tumor-forming nodules associated with an expansion of donor inflammatory cells (T and B lymphocytes and plasma cells), rare remnants of BCC epithelium and epidermoid cysts. By the seventh passage, the tumors were homogenous and metastasized widely throughout the mice. Changing transplantation location to the dermis to wound environment or supplementing the tumor with BCC-derived fibroblasts did not alter the phenotype or growth rate in SCID-beige mice. Anaplastic tumors also grew easily in SCID mice (T and B cell deficient). However, transplantation of the anaplastic tumors into normal mice (CB-17) or less severely immunodeficient mice (NCr and Balb/c: T and natural killer cell deficient) did not allow for growth. Furthermore, tumor growth could not be maintained in vitro. CONCLUSION: Empirically, these data suggest that BCC has the potential to become an aggressive metastatic neoplasm, given the right immune and stromal environment. Moreover, a functional B lymphocyte system appears to prevent this growth. As human lymphocytes also engraft in SCID-beige mice, the original host immune response could be responsible for the lack of tumor growth in the majority of xenografts. Furthermore, the anaplastic and metastatic phenotype of these BCC derived neoplasms may be the experimental equivalent of metastatic BCC and BCC associated with carcinosarcoma.