MiR-335 Correlates with Senescence/Aging in Human Mesenchymal Stem Cells and Inhibits Their Therapeutic Actions Through Inhibition of AP-1 Activity. (15th July 2014)

• Record Type: Journal Article
• Authors: Tomé, María; Sepúlveda, Juan Carlos; Delgado, Mario; Andrades, José A.; Campisi, Judith; González,, Manuel A.; Bernad, Antonio
• Is Part Of: Stem cells. Volume 32:Number 8(2014:Aug.)
• Page Start: 2229
• Page End: 2244
• Publication Date: 2014-07-15
• Subjects: Mesenchymal stem cells -- MicroRNA -- Immunotherapy -- Aging; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1699
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: MicroRNAs, small noncoding RNAs, regulate gene expression primarily at the posttranscriptional level. We previously found that miR-335 is critically involved in the regulation and differentiation capacity of human mesenchymal stem cells (hMSCs) in vitro. In this study, we investigated the significance of miR-335 for the therapeutic potential of hMSCs. Analysis of hMSCs in ex vivo culture demonstrated a significant and progressive increase in miR-335 that is prevented by telomerase. Expression levels of miR-335 were also positively correlated with donor age of hMSCs, and were increased by stimuli that induce cell senescence, such as γ-irradiation and standard O2 concentration. Forced expression of miR-335 resulted in early senescence-like alterations in hMSCs, including: increased SA-β-gal activity and cell size, reduced cell proliferation capacity, augmented levels of p16 protein, and the development of a senescence-associated secretory phenotype. Furthermore, overexpression of miR-335 abolished the in vivo chondro-osseous potential of hMSCs, and disabled their immunomodulatory capacity in a murine experimental model of lethal endotoxemia. These effects were accompanied by a severely reduced capacity for cell migration in response to proinflammatory signals and a marked reduction in Protein Kinase D1 phosphorylation, resulting in a pronounced decrease of AP-1 activity. Our results demonstrate that miR-335 plays a key role in the regulation of reparative activities of hMSCs and suggests that it might be considered a marker for the therapeutic potency of these cells in clinical applications. Stem Cells 2014;32:2229–2244