RESUMO
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by progressive ossification of soft tissues. FOP is caused by mutations in activin receptor-like kinase 2 (ALK2) that cause its constitutive activation and result in dysregulation of BMP signaling. Here, we show that generation of induced pluripotent stem cells (iPSCs) from FOP-derived skin fibroblasts is repressed because of incomplete reprogramming and inhibition of iPSC maintenance. This repression was mostly overcome by specific suppression of ALK2 expression and treatment with an ALK2 inhibitor, indicating that the inhibition of iPSC generation and maintenance observed in FOP-derived skin fibroblasts results from constitutive activation of ALK2. Using this system, we identified an ALK2 inhibitor as a potential candidate for future drug development. This study highlights the potential of the inhibited production and maintenance of iPSCs seen in diseases as a useful phenotype not only for studying the molecular mechanisms underlying iPS reprogramming but also for identifying drug candidates for future therapies.
Assuntos
Receptores de Ativinas Tipo I/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Miosite Ossificante/patologia , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Técnicas de Cocultura , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/fisiologia , Camundongos , Mutação de Sentido Incorreto , Miosite Ossificante/genética , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Pele/patologia , TranscriptomaAssuntos
Contaminação de Alimentos , Oryza/intoxicação , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Óleos de Plantas/intoxicação , Bifenilos Policlorados/intoxicação , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Bifenilos Policlorados/sangue , Fatores de TempoRESUMO
A 62-year-old man who developed akinetic mutism with delayed white matter demyelination after hypoxia was treated with hyperbaric oxygen (HBO). HBO in the subacute period markedly improved the patient's activity in daily life, cognitive function and organization on EEG. 1H-MRS showed a recovery of aerobic metabolism of the neurons. However, dementia and cerebral atrophy slowly progressed despite HBO treatment. Thus, HBO had a beneficial effect on the activity of depressed neurons but did not improve the prognosis.