Resumen de Cellular senescence in skeletal muscle regeneration, ageing and disease
- español
Este proyecto se centra en el papel de las células senescentes durante la regeneración muscular desde varios ángulos. Para llevarlo a cabo, hemos desarrollado una técnica novedosa para poder aislar células senescentes generadas in vivo a partir de tejido muscular dañado. Una vez validado, el método ha permitido aislar y generar datos transcriptómicos de las células senescentes, de distintas edades y puntos de regeneración. El análisis bioinformático ha revelado la heterogeneidad de las células senescentes y su fenotipo secretorio (SASP), además de las características universales comunes en todas las poblaciones senescentes. Por otra parte, hemos determinado que las células senescentes juegan un papel perjudicial durante el proceso de regeneración muscular de ratones jóvenes y viejos, ejerciendo señal pro-inflamatoria y pro-fibrótica a través de su SASP. Además, hemos visto que la reducción de las células senescentes mejora la progresión de la enfermedad en ratones distróficos. Finalmente, hemos propuesto un mecanismo por el cual las células senescentes actúan sobre las otras células no-senescentes y el papel del receptor CD36 en la producción del SASP.
- English
Skeletal muscle regeneration requires coordination between muscle stem cells and local-niche cells. In this thesis, we identify senescent cells as novel integral components of the regenerative process. Using a new sorting protocol and single- cell techniques, we isolated in vivo senescent cells from damaged muscles and identified three main senescent populations arising from major niche components. A deeper transcriptomic approach of the three major populations isolated from young and geriatric animals at two stages of muscle regeneration unveiled high transcriptomic heterogeneity in the senescent cells and their SASP, with conserved cell identity traits. Senescent cells are generated in response to high oxidative stress and DNA damage during the early regeneration stages. Further pathway analysis identified two universal senescence hallmarks (inflammation and fibrosis) across cell types, regeneration time and ageing. Senescent cells create an “aged- like” inflamed niche, which mirrors inflammation associated with ageing (inflammageing) through their SASP even in young mice. Interactome analysis unveiled unproductive functional interactions between senescent cells and muscle stem cells, blunting muscle stem cell expansion and regeneration. Reduction of senescent cells by pharmacological and genetic approaches accelerates muscle regeneration in young and geriatric mice and ameliorates the disease progression in dystrophic mice. Conversely, transplantation of senescent cells delays regeneration. Targeting the SASP of senescent cells through CD36 neutralization was sufficient to induce accelerated muscle recovery, uncovering CD36 potential as senomorphic in vivo. Our results provide a novel technique for isolating in vivo- generated senescent cells, defining a senescence blueprint for muscle and uncovering the role of senescent cells in distinct muscle contexts. As senescent cells also accumulate in human muscles, our findings open a potential avenue towards improving muscle repair throughout life.
