Nuclear Argonaute 2 regulates adipose tissue-derived stem cell survival through direct control of miR10b and selenoprotein N1 expression.
Argonaute 2 (Ago2) has a leading function in miRNA-induced 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 ROS-scavenging 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/β-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.
Department of Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
Bong Sun
BS
Kim
Jin Sun
JS
Jung
Jin Hwa
JH
Jang
Kyung Sun
KS
Kang
Soo Kyung
SK
Kang
D000273:Adipose Tissue / Q000166:cytology*; D017209:Apoptosis / Q000502:physiology; D060565:Argonaute Proteins; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; C435489:SELENON protein, human; D051140:Selenoproteins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases