Synergistic reversal of mesenchymal stem cell senescence by engineered exosomal delivery of a dual miR-195/miR-188 sponge.

Authors

Faranak Elmi, Arezou Azizsoltanti, Mohammad Taghizadeh, Mohammad Reza Baghaban Eslaminejad, Effat Alizadeh

Published in

Experimental gerontology. Pages 113352. Oct 08, 2026. Epub Oct 08, 2026.

Abstract

Cellular senescence critically impairs the regenerative potential and therapeutic efficacy of adipose-derived mesenchymal stem cells (AD-MSCs). MicroRNAs miR-195 and miR-188 are key regulators of aging-associated pathways, making them attractive nucleic acid targets for senescence modulation. In this study, exosomes derived from Wharton's jelly mesenchymal stem cells (WJ-MSCs) were engineered to deliver a dual miR-195/miR-188 sponge.
Quantitative RT-PCR analysis confirmed that sponge-loaded exosomes significantly reduced intracellular levels of miR-195 and miR-188, demonstrating effective functional sequestration. Exosomes were characterized by dynamic light scattering, electron microscopy, and western blotting. Functional assays demonstrated efficient intracellular delivery and a robust reversal of senescence-associated phenotypes in replicative senescent AD-MSCs.
Treatment significantly reduced senescence markers, including p16, p53, NF-κB, IL-6, and RB, while decreasing reactive oxygen species levels and β-galactosidase activity. Suppression of miR-195/miR-188 was associated with the restoration of the telomere length and reactivation of stemness-associated genes (SOX2, OCT4), suggesting modulation of telomere maintenance and cell-cycle regulatory pathways, including p53-RB signaling. Clonogenic capacity and cellular viability were markedly enhanced.
In conclusion, exosome-mediated delivery of a dual miRNA sponge represents a mechanism-driven strategy to reprogram senescence-associated gene networks and restore MSC function. This approach provides a promising cell-free nucleic acid therapeutic platform for regenerative medicine applications.

PMID:
42849861
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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