Terapia celular con micro-ARN y exosomas para el tratamiento de la inflamación crónica en un modelo de osteoartritis

Abstract

Understanding the effects of aging and inflammation on mesenchymal stem cells is crucial for developing therapies targeted at degenerative diseases. These cells exhibit beneficial effects through their paracrine activity and the release of extracellular vesicles, which have shown potential as an alternative to cell-based therapies in preclinical models. The profiles of mesenchymal stem cells and their extracellular vesicles vary with age and can be modified using microRNAs, which in turn regulate immune and inflammatory responses. This doctoral thesis presents the results obtained from investigating the effects of extracellular vesicles derived from mesenchymal stem cells on aging and pluripotency markers in cell cultures, as well as the results from evaluating their protein cargo. Furthermore, these results have allowed us to investigate the anti-inflammatory properties of these vesicles derived from mesenchymal stem cells modified to inhibit inflammation caused by miR-21 expression. Our results highlight the capacity of extracellular vesicles to influence the behavior of cell cultures based on their composition, suggesting their potential to modify cellular characteristics in vitro. Additionally, the study emphasizes the need for optimizing a protocol for the processing and higherquality protein analysis of these extracellular vesicles. The findings from the osteoarthritis animal model demonstrated that overall, extracellular vesicles derived from mesenchymal stem cells, particularly those derived from cells with inhibited miR-21 expression, exhibited significant therapeutic potential by reducing systemic inflammation and inactivating the ERK1/2 inflammatory pathway. Confirmation of the alleviation of the senescence-associated secretory phenotype in various organs from the osteoarthritis animal model further supported these results. These findings pave the way for the development of new therapies against aging-related diseases and inflammatory conditions using extracellular vesicles derived from mesenchymal stem cells.