RESUMO
Most cases of sensorineural deafness are caused by degeneration of hair cells. Although stem/progenitor cell therapy is becoming a promising treatment strategy in a variety of organ systems, cell engraftment in the adult mammalian cochlea has not yet been demonstrated. In this study, we generated human otic progenitor cells (hOPCs) from induced pluripotent stem cells (iPSCs) in vitro and identified these cells by the expression of known otic markers. We showed successful cell transplantation of iPSC-derived-hOPCs in an in vivo adult guinea pig model of ototoxicity. The delivered hOPCs migrated throughout the cochlea, engrafted in non-sensory regions, and survived up to 4 weeks post-transplantation. Some of the engrafted hOPCs responded to environmental cues within the cochlear sensory epithelium and displayed molecular features of early sensory differentiation. We confirmed these results with hair cell progenitors derived from Atoh1-GFP mice as donor cells. These mouse otic progenitors transplanted using the same in vivo delivery system migrated into damaged cochlear sensory epithelium and adopted a partial sensory cell fate. This is the first report of the survival and differentiation of hOPCs in ototoxic-injured mature cochlear epithelium, and it should stimulate further research into cell-based therapies for treatment of deafness.
Assuntos
Crescimento Celular , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva/cirurgia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Ototoxicidade/cirurgia , Transplante de Células-Tronco/métodos , Amicacina/efeitos adversos , Amicacina/farmacologia , Animais , Limiar Auditivo/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ciclosporina/farmacologia , Modelos Animais de Doenças , Fator 10 de Crescimento de Fibroblastos/farmacologia , Fator 3 de Crescimento de Fibroblastos/farmacologia , Cobaias , Células Ciliadas Auditivas/imunologia , Células Ciliadas Auditivas/metabolismo , Perda Auditiva/induzido quimicamente , Humanos , Imunossupressores/farmacologia , Células-Tronco Pluripotentes Induzidas/imunologia , Doadores VivosRESUMO
OBJECTIVES: To investigate whether genetic variants can be correlated with tendinopathy in elite male volleyball athletes. DESIGN: Case-control study. METHODS: Fifteen single nucleotide polymorphisms within BMP4, FGF3, FGF10, FGFR1 genes were investigated in 138 elite volleyball athletes, aged between 18 and 35 years, who undergo 4-5h of training per day: 52 with tendinopathy and 86 with no history of pain suggestive of tendinopathy in patellar, Achilles, shoulder, and hip abductors tendons. The clinical diagnostic criterion was progressive pain during training, confirmed by magnetic resonance image. Genomic DNA was obtained from saliva samples. Genetic markers were genotyped using TaqMan real-time PCR. Chi-square test compared genotypes and haplotype differences between groups. Multivariate logistic regression analyzed the significance of covariates and incidence of tendinopathy. RESULTS: Statistical analysis revealed participant age (p=0.005) and years of practice (p=0.004) were risk factors for tendinopathy. A significant association between BMP4 rs2761884 (p=0.03) and tendinopathy was observed. Athletes with a polymorphic genotype have 2.4 times more susceptibility to tendinopathy (OR=2.39; 95%CI=1.10-5.19). Also, association between disease and haplotype TTGGA in BMP4 (p=0.01) was observed. The FGF3 TGGTA haplotype showed a tendency of association with tendinopathy (p=0.05), and so did FGF10 rs900379. FGFR1 showed no association with disease. CONCLUSIONS: These findings indicate that haplotypes in BMP4 and FGF3 genes may contribute to the tendon disease process in elite volleyball athletes.
Assuntos
Proteína Morfogenética Óssea 4/genética , Fator 3 de Crescimento de Fibroblastos/genética , Tendinopatia/genética , Voleibol/lesões , Adulto , Estudos de Casos e Controles , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Adulto JovemRESUMO
It has been proposed that tooth agenesis and cancer development share common molecular pathways. We performed a cross-sectional study to investigate the epidemiological and molecular association between tooth agenesis and self-reported family history of cancer. Eighty-two individuals with tooth agenesis and 328 individuals with no birth defect were recruited from the same institution. Tooth agenesis was assessed in permanent teeth and was defined based on the age of the participants and when initial tooth formation should be radiographically visible. We also investigated the role of genes involved in dental development that have been implicated in tumorigenesis, and 14 markers in AXIN2, FGF3, FGF10, and FGFR2 were genotyped. Individuals with tooth agenesis had an increased risk of having a family history of cancer (p = 0.00006; OR = 2.7; 95% C.I., 1.6-4.4). There were associations between AXIN2, FGF3, FGF10, and FGFR2 with tooth agenesis [i.e., individuals who carried the polymorphic allele of FGFR2 (rs1219648) presented higher risk for having premolar agenesis (p = 0.02; OR = 1.8; 95% C.I., 1.1-3.0)]. In conclusion, tooth agenesis was associated with positive self-reported family history of cancer and with variants in AXIN2, FGF3, FGF10, and FGFR2. Prospective studies are needed to confirm if tooth agenesis can be used as a risk marker for cancer.
Assuntos
Anodontia/genética , Neoplasias/genética , Alelos , Anodontia/epidemiologia , Proteína Axina/genética , Dente Pré-Molar/anormalidades , Brasil/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Estudos Transversais , Estudos Epidemiológicos , Feminino , Fator 10 de Crescimento de Fibroblastos/genética , Fator 3 de Crescimento de Fibroblastos/genética , Variação Genética/genética , Genótipo , Humanos , Incisivo/anormalidades , Masculino , Epidemiologia Molecular , Neoplasias/epidemiologia , Odontogênese/genética , Polimorfismo Genético/genética , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fatores de Risco , AutorrelatoRESUMO
Interstitial duplications of 11q are very rare and seldom reported. In this paper we describe the first case of a duplication involving bands 11q11 and 11q12. This newly described patient has multiple craniosynostoses, congenital heart defect and developmental delay, and is a carrier of a mosaic duplication: 46,XY,dup(11)(q11-->q13.3)(29)/46,XY(6). The breakpoints were further delimited by comparative genomic hybridization microarray. We also performed fluorescent in situ hybridization analysis to determine the extension of the duplication in a patient described earlier with a duplication 11q13.5-q21. An overlapping region of less than 1.2 Mb was identified and included the duplication of genes FGF3 and FGF4 in both individuals. We discuss the possible implications of dosage effects of these genes in the onset of craniosynostosis.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Fator 3 de Crescimento de Fibroblastos/genética , Fator 4 de Crescimento de Fibroblastos/genética , Duplicação Gênica , Criança , Craniossinostoses/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , SíndromeRESUMO
Mouse mammary tumor virus (LA) induces pregnancy-dependent mammary tumors that progress toward autonomy. Here we show that in virgin females, pregnancy-dependent tumor transplants are able to remain dormant for up to 300 days. During that period, these tumors synthesize DNA, express high levels of estrogen and progesterone receptors (ER+PR+) and are able to resume growth after hormone stimulation. Surprisingly, in a subsequent transplant generation, all these tumors are fully able to grow in virgin females, they express low levels of ER and PR (ER-PR-) and have a monoclonal origin; i.e., show all of the features we have described previously in pregnancy-independent tumors. Histologically, mouse mammary tumor virus (LA)-induced tumors are morphologically similar to genetically engineered mouse (GEM) mammary tumors that overexpress genes belonging to the Wnt pathway. Interestingly, in the virus-induced neoplasias, pregnancy-independent passages arising after a dormant phase usually display a lower level of glandular differentiation together with epithelial cell trans-differentiation, a specific feature associated to Wnt pathway activation. In addition, dormancy can lead to the specific selection of Int2/Fgf3 mutated and overexpressing cells. Therefore, our results indicate that during hormone-dependent tumor dormancy, relevant changes in cell population occur, allowing rapid progression after changes in the animal internal milieu.
Assuntos
Neoplasias Mamárias Experimentais/metabolismo , Complicações Neoplásicas na Gravidez/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Apoptose , Sequência de Bases , Diferenciação Celular , Divisão Celular , Progressão da Doença , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fator 3 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/virologia , Vírus do Tumor Mamário do Camundongo/patogenicidade , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mutação , Transplante de Neoplasias , Neoplasias Hormônio-Dependentes , Gravidez , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais , Fatores de Tempo , Proteína Wnt2RESUMO
Atherosclerosis is the most frequent cause of death in industrialized countries. Lesions are characterized by lipid deposits, focal thickening of the arterial wall with proliferation of smooth muscle cells (SMC), mononuclear infiltrates and neoformed vessels. In this paper, we studied the proliferative characteristics and cytogenetic alterations of SMC. These cells, expressing specific muscular actin, were diploid with an increased proliferative index for PCNA. A high percentage of SMC showed intense expression of p53. There were signs of chromosomal instability, being the most frequent findings chromosome 7 trisomy and chromosome 11 monosomy. Additionally, the gene for FGF-3 showed a marked amplification. These findings strongly suggest that SMC proliferation is active, and is related to the accumulation or mutation of the p53 oncoprotein. It also presents specific chromosomal alterations in close relation with growth factors. According to these findings SMC hyperplasia in the atherosclerosis plaque may be considered as a cellular clonal expansion.