Senescent fibroblasts beta-galactosidase induced by extracellular vesicles obtained from MSC-iPSC under the action of various modulators

Abstract

(Abstract): The absolute majority of published experimental data involve mesenchymal stem cells, although the possibilities offered by the use of pluripotent stem cells reprogrammed from mesenchymal stem cells are practically infinite. Aim : The goal of our study was represented by tracking the effects of stimulation and inhibition of multiple functional, intracellular pathways of senescent dermal fibroblasts in culture, in the presence of microvesicles released from pluripotent stem cells reprogrammed from mesenchymal stem cells. Material and methods : We used flow cytometry to measure the production of the be-ta-galactosidase level by dermal fibroblasts in culture after 30 passages and ultraviolet treatment. Results : Reduction of β-galactosidase concentrations in senescent dermal fibroblasts was evident upon administration of exosomes (approximately 20% on average) and exosomes co-administered with: LY-294002 (a highly selective PI3K kinase inhibitor, 41% on average); nutlin-3 (which stabilizes the non-genomic actions of p53, respectively the MDM2/p53 pathway, 63% on average); rapamycin (which stimulates autophagy and the mTOR pathway and related ones, 62% on average); and metformin (a pharmacologically active substance, considered a reprogrammer of energy metabolism, 73% on average). Conclusions : Exosomes derived from pluripotent stem cells induced from mesenchymal stem cells, administered in the culture medium of senescent dermal fibroblasts, can modify the degree and evolution of the senescence of these last cells by potentiating, activating, or stimulating some intracellular pathways of biological signal transduction, but especially through epigenetic reprogramming of energy metabolism.