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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 O 2  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. S tem  C ells   2014;32:2229–2244

miR‐335 Correlates with Senescence/Aging in Human Mesenchymal Stem Cells and Inhibits Their Therapeutic Actions Through Inhibition of AP‐1 Activity