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

Autores de INCLIVA

• 

  Cristina Mas Bargues

  Autor

• Jorge Sanz Ros

  Autor

• María Carmen Román Domínguez

  Autor

• Lucia Gimeno Mallench

  Autor

• 

  Marta Inglés De La Torre

  Autor

• 

  Jose Viña Ribes

  Autor

• 

  Consuelo Borras Blasco

  Autor

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Envejecimiento Saludable

  

  Leading Researcher

  Consuelo Borras Blasco

• Grupo de investigación en envejecimiento y ejercicio físico

  

  Leading Researcher

  Jose Viña Ribes

Abstract

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-beta-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-1alpha levels in the target cells. We propose that miR-302b triggered HIF-1alpha 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.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Keywords

• aging, extracellular vesicles, oxygen, physiological oxygen concentration, physioxia, redox, senescence