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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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July 15, 2021
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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

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

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

Affiliations

Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010 Valencia, Spain. - Author
Freshage Research Group, Department Physiotherapy, Faculty of Physiotherapy, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010 Valencia, Spain. - Author
Univ Valencia, Fac Med, Dept Physiol, CIBERFES ISCIII,INCLIVA,Freshage Res Grp, Valencia 46010, Spain - Author
Univ Valencia, Fac Physiotherapy, Dept Physiotherapy, CIBERFES ISCIII,INCLIVA,Freshage Res Grp, Valencia 46010, Spain - Author

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.

Keywords

agingcancerclusterextracellular vesiclesinductionmetabolismphysiological oxygen concentrationphysioxiaredoxsenescenceAdolescentAdultAgingCells, culturedDental pulpExtracellular vesiclesFemaleHif1a protein, humanHuman fibroblastsHumansHypoxia-inducible factor 1, alpha subunitKlf4 protein, humanKruppel-like factor 4MaleMicrornasMirn302a microrna, humanOxygenPhysiological oxygen concentrationPhysioxiaRedoxSenescenceStem cellsYoung adult

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Biomolecules due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 96/295, thus managing to position itself as a Q2 (Segundo Cuartil), in the category Biochemistry & Molecular Biology. Notably, the journal is positioned en el Cuartil Q2 para la agencia Scopus (SJR) en la categoría Biochemistry.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.78. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.02 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 6.21 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-26, the following number of citations:

  • WoS: 48
  • Scopus: 49
  • Europe PMC: 42

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-26:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 50 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

    • The work has been submitted to a journal whose editorial policy allows open Open Access publication.