RESUMEN
Ageing is intimately connected to the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS-STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS-STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing.
Asunto(s)
Envejecimiento , Proteínas de la Membrana , Nucleotidiltransferasas , Células del Estroma , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Proteína 2 Relacionada con la Actina/metabolismo , Envejecimiento/metabolismo , Senescencia Celular , Matriz Extracelular , Envejecimiento Saludable , Inmunidad Innata , Lamina Tipo B/metabolismo , Mecanotransducción Celular/genética , Proteínas de la Membrana/metabolismo , Membrana Nuclear/metabolismo , Nucleotidiltransferasas/metabolismo , Transducción de Señal , Células del Estroma/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/antagonistas & inhibidores , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Proteínas Señalizadoras YAP/antagonistas & inhibidores , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Glioblastoma (GBM) is a devastating human malignancy. GBM stem-like cells (GSCs) drive tumor initiation and progression. Yet, the molecular determinants defining GSCs in their native state in patients remain poorly understood. Here we used single cell datasets and identified GSCs at the apex of the differentiation hierarchy of GBM. By reconstructing the GSCs' regulatory network, we identified the YAP/TAZ coactivators as master regulators of this cell state, irrespectively of GBM subtypes. YAP/TAZ are required to install GSC properties in primary cells downstream of multiple oncogenic lesions, and required for tumor initiation and maintenance in vivo in different mouse and human GBM models. YAP/TAZ act as main roadblock of GSC differentiation and their inhibition irreversibly lock differentiated GBM cells into a non-tumorigenic state, preventing plasticity and regeneration of GSC-like cells. Thus, GSC identity is linked to a key molecular hub integrating genetics and microenvironmental inputs within the multifaceted biology of GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Animales , Neoplasias Encefálicas/genética , Carcinogénesis/patología , Plasticidad de la Célula , Glioblastoma/genética , Humanos , Ratones , Células Madre Neoplásicas/patología , Análisis de la Célula IndividualRESUMEN
The possibility to identify with significant accuracy the position of a vehicle in a mapping reference frame for driving directions and best-route analysis is a topic which is attracting a lot of interest from the research and development sector. To reach the objective of accurate vehicle positioning and integrate response events, it is necessary to estimate position, orientation and velocity of the system with high measurement rates. In this work we test a system which uses low-cost sensors, based on Micro Electro-Mechanical Systems (MEMS) technology, coupled with information derived from a video camera placed on a two-wheel motor vehicle (scooter). In comparison to a four-wheel vehicle; the dynamics of a two-wheel vehicle feature a higher level of complexity given that more degrees of freedom must be taken into account. For example a motorcycle can twist sideways; thus generating a roll angle. A slight pitch angle has to be considered as well; since wheel suspensions have a higher degree of motion compared to four-wheel motor vehicles. In this paper we present a method for the accurate reconstruction of the trajectory of a "Vespa" scooter; which can be used as alternative to the "classical" approach based on GPS/INS sensor integration. Position and orientation of the scooter are obtained by integrating MEMS-based orientation sensor data with digital images through a cascade of a Kalman filter and a Bayesian particle filter.