RESUMEN
The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function.
Asunto(s)
Envejecimiento/fisiología , Ciclo Celular , Células Musculares/citología , Células Satélite del Músculo Esquelético/citología , Nicho de Células Madre/fisiología , Proteínas Adaptadoras Transductoras de Señales , Animales , Recuento de Células , Diferenciación Celular , Senescencia Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Citometría de Flujo , Homeostasis , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/citología , Factor de Transcripción PAX7/metabolismo , Fosfoproteínas/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/trasplante , Transducción de Señal , Factores de TiempoRESUMEN
Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle-aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin-remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo-insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits.