Abstract
The composition and biological activity of donor cells is largely determined by the exosomes they secrete. In this study, we isolated exosomes from young (Young-Exo) and aged (Age-Exo) mesenchymal stem cells (MSCs) and compared their regeneration activity. Young Exo MSCs were more efficient than Aged-Exo at promoting the formation of endothelial tube, reducing fibrosis, and inhibiting apoptosis of cardiomyocytes in vitro; and improving cardiac structure and function in vivo in the hearts of rats following myocardial infarction (MI). MicroRNA sequencing and polymerase chain reaction (PCR) analysis revealed that miR-221-3p was significantly down-regulated in Aged-Exo. The aged MSCs were rejuvenated and their reparative cardiac ability restored when miR-221-3p was overexpressed in Aged-Exo. The protective effect was lost when miR-221-3p expression was knocked down in Young-Exo. These effects of miR-221-3p were achieved through enhancing Akt kinase activity by inhibiting phosphatase and tensin homolog (PTEN). In conclusion, exosomal miR-221-3p secreted from Aged MSCs attenuated the function of angiogenesis and promoted survival of cardiomyocytes. Up-regulation of miR-221-3p in aged MSCs improved their ability of angiogenesis, migration and proliferation, and suppressed apoptosis via the PTEN/Akt pathway.
Highlights
Mesenchymal stem cell (MSCs) transplantation has enabled great progress in the treatment of ischemic heart diseases (Kanelidis et al, 2017). Their cardioprotective effect declines with cell aging and this limits the application of autologous cell therapy in elderly patients with ischemic heart disease (Fisher et al, 2015; Nguyen et al, 2016)
SA-β-Gal staining showed that senescence greatly increased in aged mesenchymal stem cells (MSCs) (Figure 1B and Supplementary Figure S1)
Expression of senescent biomarker P21 and P53 significantly increased in aged MSCs compared with young MSCs but there was no significant difference in P16 protein expression (Figure 1C)
Summary
Mesenchymal stem cell (MSCs) transplantation has enabled great progress in the treatment of ischemic heart diseases (Kanelidis et al, 2017). Their cardioprotective effect declines with cell aging and this limits the application of autologous cell therapy in elderly patients with ischemic heart disease (Fisher et al, 2015; Nguyen et al, 2016). Accumulating evidence shows that aging affects the functions of MSCs, including differentiation, proliferation and migration, as well as angiogenic potential, and in turn reduces their clinical efficacy When donor cells are stimulated by the environment, the content of the exosomes will change and so their biological effect (Boriachek et al, 2018)
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