RESUMEN
Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). In normal fibroblasts, the efficiency of iPSC generation was enhanced by transducing mutant ACVR1 (617G > A) or SMAD1 or adding BMP4 protein at early times during the reprogramming. In contrast, adding BMP4 at later times decreased iPSC generation. ID genes, transcriptional targets of BMP-SMAD signaling, were critical for iPSC generation. The BMP-SMAD-ID signaling axis suppressed p16/INK4A-mediated cell senescence, a major barrier to reprogramming. These results using patient cells carrying the ACVR1 R206H mutation reveal how cellular signaling and gene expression change during the reprogramming processes.
Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Miositis Osificante , Proteínas Smad/metabolismo , Receptores de Activinas Tipo I/genética , Adolescente , Adulto , Animales , Línea Celular , Reprogramación Celular , Senescencia Celular , Niño , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Femenino , Humanos , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Miositis Osificante/genética , Transducción de SeñalRESUMEN
The present study reports elevated levels of endotoxin/lipopolysaccharide (LPS) concentrations in plasma from patients with sporadic amyotrophic lateral sclerosis (sALS) and Alzheimer's (AD) as compared to healthy controls. Levels of plasma LPS showed a significant positive correlation with degree of blood monocyte/macrophage activation in disease groups and was most elevated in patients with advanced sALS disease. There was a significant negative relationship between plasma LPS and levels of monocyte/macrophage IL-10 expression in sALS blood. These data suggest that systemic LPS levels and activated monocyte/macrophages may play significant roles in the pathogenesis of sALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Endotoxinas/sangre , Lipopolisacáridos/sangre , Anciano , Enfermedad de Alzheimer/sangre , Esclerosis Amiotrófica Lateral/patología , Análisis de Varianza , Femenino , Citometría de Flujo/métodos , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-10/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismoRESUMEN
Recent studies suggest that monocyte activation may play a role in ALS pathogenesis. Therefore, monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), and plasma levels of MCP-1 were measured in 42 sALS patients, 38 healthy and 34 age-related macular degeneration (ARMD) controls. MCP-1 was elevated in both sALS and ARMD patients, but CCR2 levels were significantly decreased on sALS but not on ARMD monocytes. Loss of monocyte CCR2 expression was inversely correlated with degree of monocyte/macrophage activation in sALS and this decrease was unlikely due to receptor down-regulation given the ARMD results. Defective monocyte/macrophages may play an active role in sALS.