Nuclear Argonaute 2 regulates adipose tissue‐derived stem cell survival through direct control of miR10b and selenoprotein N1 expression

Abstract

SummaryArgonaute 2 (Ago2) has a leading function in miRNAinduced RNA silencing, a conserved gene regulatory mechanism in cells and organisms. miRNAs are critical for stem cell self-renewal, development, and other functions. Here, we report that nuclear Ago2, by binding to a specific region of functional genes, directly controls adipose tissue-derived stem cell (ATSC) survival in response to a critical dose of reactive oxygen species (ROS)-mediated oxidative cell damage or senescence. The role of nuclear Ago2 has not been previously reported. Here, we show that human ATSCs in which Ago2 was downregulated underwent apoptosis. Silencing of Ago2 in ATSCs significantly induces upregulation of miR10b and miR23b expression. These miRNAs directly interfere with ROSscavenging gene expression, such as TXNL1 and GPX3. Upregulation of miR10b and miR23b is sufficient to induce ATSC cell apoptosis via p38 MAPK phosphorylation and caspase 3 activation. In addition, Ago2 overexpression or interference by miR10b and miR23b expression in ATSCs partially rescued H 2 O 2 ⁄ ROS-mediated apoptotic cell death by upregulating the expression of TXNL2, JUNK, caspase-3, and cytochrome C. Nuclear Ago2-mediated miR10b and miR23b downregulation also allows cells to escape senescence, which results in telomerase reverse transcriptase, stemness overexpression, and improved self-renewal and differentiation through Wnt5a ⁄ b-catenin activation. Argonaute 2 expression is critical for stem cells to escape senescence by downregulating miR10b and miR23b. The Ago2-binding gene selenoprotein N1 (SEPN1) was also effectively involved in ATSC survival and self-renewal through ROS-mediated p38 MAPK inactivation.

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

“…To address the mechanism responsible for the enhanced FAK transcription, we first analyzed the 2 kb upstream regulatory sequence of the FAK gene. Interestingly, we identified two conserved regions containing 5 0 -CTTCCTC(G)-3 0 or 5 0 CTTCTC(G)-3 0 or a G-rich region (three or more Gs), which were considered to be Ago2 binding sites based on previous studies, 24,25 as indicated in Fig. 6A.…”

Activation of Liver X Receptor Improves Viability of Adipose-Derived Mesenchymal Stem Cells to Attenuate Myocardial Ischemia Injury Through TLR4/NF-κB and Keap-1/Nrf-2 Signaling Pathways

“…Previous work has already revealed that the microenvironment around stem cells plays a critical role in cell survival and function (14). High levels of pro-inflammatory factors and ROS, two strong components of host response to injury, will retard stem cell survival and decrease their regenerative capabilities (6,18,30,33). When we measured inflammatory cytokine (TNF-a and IL-6) and ROS levels in tissue, we found that an LXR agonist could decrease TNF-a, IL-6, and ROS generation in ischemically injured myocardium, providing a better local microenvironment that was crucial to increased AD-MSC survival.…”

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

“…The protein combines RNA binding properties with an intrinsic enzyme activity and is thus a central part of the RNA silencing machinery [2]. Besides its role as the enzymatic component of the cytosolic RISC, translocation of Ago2 into the nucleus has been described [17,22]. In addition, detailed analysis of the subcellular localization of Ago2 revealed that the protein also associates physically with the rough endoplasmic reticulum [23].…”