Crucial role of nuclear Ago2 for hUCB-MSCs differentiation and self-renewal via stemness control

• Published in: Antioxidants & redox signaling Vol. 16; no. 2; p. 95
• Main Authors: Jang, Jin Hwa, Jung, Jin Sun, Im, Young Bin, Kang, Kyung Sun, Choi, Jee In, Kang, Soo Kyung
• Format: Journal Article
• Language: English
• Published: United States 15.01.2012
• Subjects: Apoptosis; Argonaute Proteins - genetics; Argonaute Proteins - physiology; Base Sequence; beta Catenin - metabolism; Cell Differentiation - physiology; Humans; Janus Kinases - metabolism; Mesenchymal Stem Cells - cytology; Molecular Sequence Data; Octamer Transcription Factor-3 - metabolism; Proto-Oncogene Proteins - metabolism; STAT3 Transcription Factor - metabolism; Umbilical Cord - cytology; Wnt Proteins - metabolism; Wnt-5a Protein
• ISSN: 1557-7716
• DOI: 10.1089/ars.2011.3975

Argonaute2 (Ago2) has intrinsic endonuclease activity in microRNA processing that plays a fundamental role in gene regulation. In this study, we demonstrate novel functions and molecular mechanisms of nuclear Ago2 in the self-renewal and plasticity of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Nuclear Ago2 binds to a set of regulatory genes, including Ago2 itself, Oct4, Sox2, Nanog, GATA, STAT3, and β-catenin, that potentially target fundamental functions of stem cells. Direct regulation of the stemness genes by nuclear Ago2 was also crucial for cell self-renewal, survival, and differentiation into various types of tissues or cells, including neural cells and β-cells. Moreover, regulation of Oct4 by Ago2 directly controls the stem cell plasticity-determining signal mediators JAK2/STAT3 and Wnt5A/β-catenin and positively regulates cell proliferation and differentiation via blockage of ROS generation and P38/JNK inactivation. Nuclear Ago2 or stemness expression lead increased stem cell identity and decreased differentiation into a mesodermal lineage but also led to increased neural differentiation and β-cell differentiation in hUCB-MSCs. Nuclear Ago2-mediated stemness expression in hUCB-MSCs is also involved in cell survival, helping cells escape apoptotic cell death via inactivation of P38/JNK, caspase-3, and Bax. This study reveals that nuclear Ago2 globally controls stem cell self-renewal and differentiation through direct regulation of stemness genes and important signal mediator activation following inactivation of ROS/P38/JNK and activation of the JAK/STAT3 and Wnt/ β-catenin signal pathways.