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This research was funded by the following grants: Instituto de Salud Carlos III, FEDER [grant number PIE15/00013], SAF2016-75508-R from the Spanish Ministry of Education and Science (MEC), CB16/10/00435 (CIBERFES-ISCIII), PROMETEOII2014/056 de "Conselleria, de Sanitat de la Generalitat Valenciana, GV/2018/067 from "Conselleria d'Educacio, Cultura i Esport de la Generalitat Valenciana" to M.I., GV/2019/092 from "Conselleria d'Educacio, Cultura i Esport de la Generalitat Valenciana" to C.M.-B., EU-Funded FRAILOMIC Initiative (FP7-HEALTH-2012-Proposal no. 305483-2), ADVANTAGE-724099 (HP-JA) -DIALBFRAIL-LATAM (825546 H2020-SC1-BHC) to J.V., PCIN-2017-117 of the Ministry of Economy and Competitiveness, the EU Joint Programming Initiative `A Healthy Diet for a Healthy Life' (JPI HDHL INTIMIC-085) to C.B. Additionally, A.R.-D. is the recipient of a predoctoral grant financed by Generalitat Valenciana (ACIF/2019/164). Similarly, Dr. C.M.-B. is the recipient of a postdoctoral grant financed by Generalitat Valenciana (APOSTD/2018/230) and FSE (European Social Fund).

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Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation

Publicado en:Biomolecules. 10 (6): 1-16 - 2020-06-01 10(6), DOI: 10.3390/biom10060957

Autores: Mas-Bargues, Cristina; Sanz-Ros, Jorge; Roman-Dominguez, Aurora; Gimeno-Mallench, Lucia; Ingles, Marta; Vina, Jose; Borras, Consuelo

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Aging is accompanied by the accumulation of senescent cells that alter intercellular communication, thereby impairing tissue homeostasis and reducing organ regenerative potential. Recently, the administration of mesenchymal stem cells (MSC)-derived extracellular vesicles has proven to be more effective and less challenging than current stem cell-based therapies. Extracellular vesicles (EVs) contain a cell-specific cargo of proteins, lipids and nucleic acids that are released and taken up by probably all cell types, thereby inducing functional changes via the horizontal transfer of their cargo. Here, we describe the beneficial properties of extracellular vesicles derived from non-senescent MSC, cultured in a low physiological oxygen tension (3%) microenvironment into prematurely senescent MSC, cultured in a hyperoxic ambient (usual oxygen culture conditions, i.e., 21%). We observed that senescent MCS, treated with EVs from non-senescent MCS, showed reduced SA-β-galactosidase activity levels and pluripotency factor (OCT4, SOX2, KLF4 and cMYC, or OSKM) overexpression and increased glycolysis, as well as reduced oxidative phosphorylation (OXPHOS). Moreover, these EVs' cargo induced the upregulation of miR-302b and HIF-1α levels in the target cells. We propose that miR-302b triggered HIF-1α upregulation, which in turn activated different pathways to delay premature senescence, improve stemness and switch energetic metabolism towards glycolysis. Taken together, we suggest that EVs could be a powerful tool to restore altered intercellular communication and improve stem cell function and stemness, thus delaying stem cell exhaustion in aging.

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