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

Cristina Mas-Bargues,José Viña,Lucia Gimeno-Mallench,Marta Inglés,Consuelo Borrás,Jorge Sanz-Ros,Aurora Román-Domínguez

doi:10.3390/biom10060957

Cristina Mas-Bargues, José Viña + Show 5 more

Open Access

https://doi.org/10.3390/biom10060957

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Journal: Biomolecules	Publication Date: Jun 25, 2020
Citations: 40	License type: CC BY 4.0

Affiliation: University of Valencia

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-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.

Highlights

Cellular senescence is the consequence of several stresses by which cells lose their ability to proliferate [1]
This senescent phenotype includes morphological alterations, reduced proliferation rate [2], increased p16INK4a mRNA expression and high senescence associated-β-galactosidase activity levels [3]. This oxidative stress-induced premature senescence is characterized by a minimum expression of SOX2, OCT4, KLF4 and cMYC (OSKM) transcription factors in comparison to physiological oxygen tension levels (3% O2), called physioxia [3]
As our results show, introducing Extracellular vesicles (EVs) derived from a young and healthy micro ambient cell can delay senescence progression

Summary

Introduction

Cellular senescence is the consequence of several stresses by which cells lose their ability to proliferate [1]. Our group described in recent studies that high oxygen tension (21% O2) in primary stem cell culture creates an oxidative stress microenvironment that induces a premature senescence. This senescent phenotype includes morphological alterations, reduced proliferation rate [2], increased p16INK4a mRNA expression and high senescence associated-β-galactosidase activity levels [3]. This oxidative stress-induced premature senescence is characterized by a minimum expression of SOX2, OCT4, KLF4 and cMYC (OSKM) transcription factors in comparison to physiological oxygen tension levels (3% O2), called physioxia [3]. An altered metabolic state has been associated with senescent cells in culture [6,7]

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