Silencing MicroRNA-195 Restores Activity in Old Stem Cells
Stem cell activity declines with age, resulting in increased tissue frailty and dysfunction. Researchers are finding a variety of ways to increase the activity of old stem cell populations, with most of this work focusing on the better known and characterized muscle and bone marrow stem cells. It is likely that different populations all require subtly different methodologies given their different cell states, but so far it seems that ramping up the processes of telomere lengthening works broadly, and that this does boost stem cell activity may be the underlying reason why telomerase therapy extends life in mice, though there are other potential mechanisms to consider, and telomere dynamics in mice are quite different from those in humans. In our species the consensus is that more telomerase activity is probably the path to more cancer.
Sufficient control over native stem cells may prove an adequate substitute for stem cell transplants, but there is still the question of just how much risk this entails given the age-related damage accumulated by stem cells and stem cell niches in old tissues. Based on data gathered so far, there is less risk of cancer than was expected, but in the grand scheme of things these are still the early days of manipulating stem cells. Old stem cell populations most likely require repair or replacement as a part of any comprehensive regenerative medicine targeted at the aging process, but it seems plausible that there are benefits to be had by awakening dormant stem cells even without that sort of comprehensive rejuvenation treatment.
Previously, we reported that a novel sub-population of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high anti-aging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in post-transcriptional gene expression programs, however it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem cell aging.MiRNAs profiling analysis in YMSCs and OMSCs by microarray showed that miR-140, miR-146a/b and miR-195 were significantly upregulated in OMSCs, which led us to hypothesize that these are age-induced miRNAs involved in stem cell senescence. Of these miRNAs, we found miR-195 directly targeted 3'-untranslated region of Tert gene by computational target prediction analysis and luciferase assay, and knockdown of miR-195 significantly increased Tert expression in OMSCs. Strikingly, miR-195 inhibition significantly induced telomere re-lengthening in OMSCs along with reduced expression of senescence-associated β-galactosidase. Moreover, silencing miR-195 in OMSCs by transfection of miR-195 inhibitor significantly restored anti-aging factors expression including Tert and Sirt1 as well as phosphorylation of Akt and FOXO1. Notably, abrogation of miR-195 markedly restored proliferative abilities in OMSCs. Transplantation of OMSCs with knocked out miR-195 reduced infarction size and improved left ventricular function in an animal model of myocardial infarction.
In conclusion, rejuvenation of aged stem cells by miR-195 inhibition would be a promising autologous therapeutic strategy for cardiac repair in the elderly patients.