title: Crucial role of nuclear Ago2 for hUCB-MSCs differentiation and self-renewal via stemness control.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Laboratory of Stem Cell Biology, Department of Biotechnology, College of Veterinary Medicine, Seoul, Korea.
authors: Jin Hwa
authors: JH
authors: Jang
authors: Jin Sun
authors: JS
authors: Jung
authors: Young Bin
authors: YB
authors: Im
authors: Kyung Sun
authors: KS
authors: Kang
authors: Jee In
authors: JI
authors: Choi
authors: Soo Kyung
authors: SK
authors: Kang
mesh_terms: D017209:Apoptosis; D060565:Argonaute Proteins / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008969:Molecular Sequence Data; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D053612:Janus Kinases