Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase

Abstract

Previously, we reported that a novel subpopulation of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high antiaging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in posttranscriptional gene expression programs, and 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 SIGNIFICANCE STATEMENTIn this study, we investigated the role of miRNAs involved in stem cell aging and their impact on cardiac repair. Here we report our novel findings that regenerative ability of aged stem cells is deteriorated by increased expression of miR-195 which targets telomerase reverse transcriptase (Tert) gene, and abrogation of miR-195 in aged stem cells markedly induces Tert reactivation, resulting in significant telomere re-lengthening. Additionally, we show that transplantation of aged stem cells lacking miR-195 significantly reduced infarction size and concomitant improvement of cardiac function. These findings demonstrate that silencing miR-195 reverses the senescence clock in aged stem cells by telomerase reactivation. The strategy of modification of miRs in stem cells holds great promise for stem cell based repair of aging myocardium.

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…Given the critical importance of vascular disease in affecting the nervous system, SIRT1 and its ability to oversee small non-coding ribonucleic acids (RNAs), termed microRNAs (miRNAs) (134, 158–160), have become exciting targets for vascular disease and the nervous system (Figure 1). SIRT1 pathways are involved in vascular survival and senescence (88, 152, 161), atherosclerosis (162–166), lifespan extension (4, 167–169), diabetic retinopathy (170), cellular metabolism and DM (14, 17, 20, 115, 145, 171, 172), oxidative stress pathways (58, 148, 173–179), and neuronal survival and cognition (11, 113, 180–183).…”

“…Under some conditions, increased SIRT1 activity is beneficial. Silencing of miR-195 in old mesenchymal stem cells promotes stem cell proliferation by increasing SIRT1 activity to restore anti-aging factors expression that include telomerase reverse transcriptase, the forkhead transcription factor FOXO1 (59), and protein kinase B (Akt) (160). Stem cell proliferation also may require increased SIRT1 activity in combination with the inhibition or dysfunction of mTOR signaling that is controlled by miRNAs (184).…”

Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease

“…SIRT1 modulation of vascular disease as well as stem cell proliferation may be closely tied to the pathways of small non-coding ribonucleic acids (RNAs) that are termed microRNAs (miRNAs) (43, 49, 130, 131). MiRNAs oversee gene expression by silencing targeted messenger RNAs (mRNAs) translated by specific genes and are composed of 19–25 nucleotides.…”

“…Under some conditions, increased SIRT1 activity is beneficial. Silencing of miR-195 in old mesenchymal stem cells promotes stem cell proliferation by increasing SIRT1 activity to restore anti-aging factors expression that include telomerase reverse transcriptase, the forkhead transcription factor FOXO1 (50), and protein kinase B (Akt) (131). Increased SIRT1 activity with loss of miR-204 promotes the proliferation of spermatogonial stem cells (132).…”

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

“…Accumulation of senescent cells with increased age is believed to contribute to loss of tissue and organ function (5, 6). Oxidative, metabolic, and mechanical stressors also increase with age that can promote tissue injury (7–11).…”