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

Abstract

MicroRNAs (miRNAs), small non-coding 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 senescent-associated secretory phenotype (SASP). 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 pro-inflammatory signals and a marked reduction in Protein Kinase D1 (PRKD1) 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.

Coenzyme Q10 Inhibits the Aging of Mesenchymal Stem Cells Induced by D-Galactose through Akt/mTOR Signaling

“…However, increasing studies have shown that aging of MSCs affects their clinical application [7, 39–41]. Reactive oxygen species are a major compartment that is known to regulate MSC senescence [12, 42, 43].…”

miR-135a modulates tendon stem/progenitor cell senescence via suppressing ROCK1

“…For example, miR-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1 [15]. miR-335 correlates with senescence/aging in human mesenchymal stem cells and inhibits their therapeutic actions through inhibition of activator protein-1 activity [16]. However, the effects of specific miRNAs on ROCK1 expression during TSPC senescence are less known.…”

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

“…Sixth , stem cell exhaustion is also considered one of the hallmarks of aging, as the decline in the capacity of tissues and organs to regenerate leads to an accumulation of senescent cells (Campisi and Robert, 2014; van Deursen, 2014). Epigenetics and endogenous oxidative stress are among the factors that contribute to stem cell exhaustion (Davalli et al, 2016; Tome et al, 2014). Because metabolic defects are also responsible for stem cell exhaustion (Ito and Ito, 2016), a balance between self-renewal and differentiation of stem cells must occur through coordination of metabolic pathways and distribution of mitochondria in order to provide lifelong tissue homeostasis.…”