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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.

Link: http://dx.doi.org/10.1002/stem.2211

Comments

Off-topic but... did the FA! Fundraiser already started? I see $15,000 now.

Posted by: Antonio at September 23rd, 2015 9:04 AM

@Antonio: It starts on October 1st. Some people are eager beavers, however, and needed to get pledges organized in advance. For the rest of us, matching only starts on the 1st.

Posted by: Reason at September 23rd, 2015 12:07 PM

Ah, OK. Thanks.

Posted by: Antonio at September 23rd, 2015 1:07 PM

Out of all SENS fixes, cleaning up the extracellular matrix may be the hardest and most important. I have a feeling that fixing the cell inside (or for that matter repopulating stem cells with young ones) will be easier than fixing the outside fibers and other structures. In aging organism the outside of cell damage is more mechanical in nature, and the inside is more like a molecular machine that may need just reprogramming/fine tuning, for example, reprogramming the epimutations. And if you clean up and restore the outside of the cell, the cell, with a little help, may fix itself, or adjust to the young environment. But not the other way round, fixing the cell (as in reimplanting young stem cells into an aging tissue) will not fix all the tangles and hardened structure outside.

Posted by: veriti at September 23rd, 2015 6:47 PM

Mobilize stem cells is good plus they are capable of exporting damage to daughter cells in order to repair themselves. This will also improve the signalling environment.

The telomerase cancer connection is mentioned once again I see. Telomerase is permissive not causative and various studies have demonstrated that improving telomeres is good for cancer protection due to improving gene expression and stability. More importantly a number of far more qualified researchers believe and have demonstrated that. Bottom line is we will not know unless it's tested.

Less debate and more testing.

Posted by: Steve h at September 25th, 2015 4:58 AM

I will add we can likely gain similar results by importing fresh stem cells in artificial niche as they engraft and encourage dormant native stem cells to repair and regenerate too.

Given artificial niche have been developed by Stanford using gels demonstrating that fresh cells in these gel niche are able to offset the old environment it's a real possibility that stem cells could be mobilized in that manner without needing telomerase induction or gene therapy.

Posted by: Steve h at September 25th, 2015 5:03 AM

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