期刊
STEM CELLS
卷 32, 期 8, 页码 2229-2244出版社
WILEY
DOI: 10.1002/stem.1699
关键词
Mesenchymal stem cells; MicroRNA; Immunotherapy; Aging
资金
- Spanish Ministry of Science and Innovation [SAF 2010-16065]
- Ministry of Economy and Competitiveness [SAF 2008-02099, PLE2009-0147, PSE-010000-2009-3, FIS PI13/00666]
- Comunidad Autonoma de Madrid [S2010/BMD-2420]
- Red de Terapia Celular del Instituto de Salud Carlos III (TerCel)
- European Commission [FP7-HEALTH-2009/CARE-MI]
- Miguel Servet Program of the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain) [CP07/00306]
- Spanish Programa de Formacion del Profesorado Universitario (Ministry of Education, Culture, and Sports, Spain)
- Spanish Ministry of Economy and Competitiveness
- Pro-CNIC Foundation
- [PLE2009-0112]
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 gamma-irradiation and standard O-2 concentration. Forced expression of miR-335 resulted in early senescence-like alterations in hMSCs, including: increased SA-beta-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 chondroosseous 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.
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