Disrupt senescence through estracellular vesicles biogenesis reduction

7th GEIVEX Symposium, 23-25 October 2024, Palma de Mallorca

Secreted molecules as interleukins, cytokines, chemokines, grow factors and the release of small extracellular vesicles (sEV) modulate the cellular microenvironment. Senescent cells main characteristics are the inhibition of the cell cycle, an increasedβ-galactosidase activity and a specific secretome of the previous compounds known as Senescence Associated secretory phenotype (SASP). SASP leads the microenvironment to a more pro-inflammatory state and induces senescence in the neighbouring cells through a paracrine and autocrine manner. As time goes by, the accumulation of senescent cells drives into age-related diseases. In this study, we focused on paracrine senescence transmission mediated by sEV. Our objective is to avoid the transmission of senescence modulating the secretion of the sEV. For that, we knocked-down the expression of RAB27A, protein implicated in sEV biogenesis, in mesenchymal stem cells from human umbilical cord stroma. We treated these cells and control ones with sEV from senescent cells and we accomplished a reduction in the paracrine senescence trans- mission validated by β-galactosidase and proliferation assays. Next, we performed a shotgun proteomic study of the recipient cells, identifying several proteins statistically significant dysregulated. These proteins are related to lysosomes, Golgi and calcium displaying a possible participation of the endomembrane system. One of these dysregulated proteins is ORAI1 a calcium channel. At present we are inhibiting ORAI1 with a pharmacological drug (MRS1845) after induce senescence. We are seeing that the production of vesicles decreases as well as other senescence markers like p21. In conclusion, the silencing of RAB27A prevents the paracrine senescence transmission and calcium channel ORAI1, could be a possible target for the development of drugs against SASP sEV component

Ministerio de ciencias e innovación (MICINN) (RYC2021-032567-I), Xunta de Galicia (ED481D-2021-020 & ED431F 2023/30), InTalent program from UDC-Inditex. Spanish National Health Institute Carlos III (PI20/00497 & PI23/01347, co-funded by the European Union), Proof-of-concept from ProteoRed-ISCIII (PPC2020) and Transference Project by Profesor Novoa Santos foundation (RESISFERRO and ENDOPROT

Peer reviewed