Dongdong Fei1,2, Yazheng Wang1, Qiming Zhai2, Xige Zhang1, Yang Zhang1, Yang Wang1, Bei Li3, Qintao Wang4. 1. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. 2. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. 3. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. lbfmmu@163.com. 4. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. yznmbk@fmmu.edu.cn.
Abstract
BACKGROUND: This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrow-derived mesenchymal stem cells (BMSCs) and its potential mechanism. METHODS: The acetylation level and KAT6A expression of BMSCs from the young (YBMSCs) and the old (OBMSCs) were examined. Gain- and loss-of-function experiments were performed to determine the effect of KAT6A on BMSC proliferation, colony formation, and osteogenic differentiation. The effect of KAT6A on Nrf2/ARE signaling pathway was investigated after KAT6A inhibition in YBMSCs or overexpression in OBMSCs, and the role of Nrf2/ARE signaling pathway on stemness was examined by investigating proliferation, colony formation, and osteogenic differentiation. Further in vivo study was performed to explore osteogenesis ability of OBMSCs after modulation of KAT6A and Nrf2/ARE pathway through cell sheet technology. RESULTS: The acetylation level and KAT6A expression of OBMSCs were decreased, and KAT6A downregulation resulted in decreased proliferation, colony formation, and osteogenic differentiation of OBMSCs. Mechanically, KAT6A was found to regulate Nrf2/ARE signaling pathway and inhibit ROS accumulation in OBMSCs, thus promoting proliferation, colony formation, and osteogenic differentiation of OBMSCs. Further study demonstrated that KAT6A could promote osteogenesis of OBMSCs by regulating Nrf2/ARE signaling pathway. CONCLUSIONS: Downregulation of KAT6A resulted in the decreased stemness of OBMSCs by inhibiting the Nrf2/ARE signaling pathway. KAT6A was downregulated in aging bone marrow-derived mesenchymal stem cells (BMSCs), and downregulation of KAT6A resulted in Nrf2/ARE signaling pathway inhibition and ROS accumulation, thus leading to decreased stemness of aging BMSCs.
BACKGROUND: This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrow-derived mesenchymal stem cells (BMSCs) and its potential mechanism. METHODS: The acetylation level and KAT6A expression of BMSCs from the young (YBMSCs) and the old (OBMSCs) were examined. Gain- and loss-of-function experiments were performed to determine the effect of KAT6A on BMSC proliferation, colony formation, and osteogenic differentiation. The effect of KAT6A on Nrf2/ARE signaling pathway was investigated after KAT6A inhibition in YBMSCs or overexpression in OBMSCs, and the role of Nrf2/ARE signaling pathway on stemness was examined by investigating proliferation, colony formation, and osteogenic differentiation. Further in vivo study was performed to explore osteogenesis ability of OBMSCs after modulation of KAT6A and Nrf2/ARE pathway through cell sheet technology. RESULTS: The acetylation level and KAT6A expression of OBMSCs were decreased, and KAT6A downregulation resulted in decreased proliferation, colony formation, and osteogenic differentiation of OBMSCs. Mechanically, KAT6A was found to regulate Nrf2/ARE signaling pathway and inhibit ROS accumulation in OBMSCs, thus promoting proliferation, colony formation, and osteogenic differentiation of OBMSCs. Further study demonstrated that KAT6A could promote osteogenesis of OBMSCs by regulating Nrf2/ARE signaling pathway. CONCLUSIONS: Downregulation of KAT6A resulted in the decreased stemness of OBMSCs by inhibiting the Nrf2/ARE signaling pathway. KAT6A was downregulated in aging bone marrow-derived mesenchymal stem cells (BMSCs), and downregulation of KAT6A resulted in Nrf2/ARE signaling pathway inhibition and ROS accumulation, thus leading to decreased stemness of aging BMSCs.
Authors: Jonathan B Baell; David J Leaver; Stefan J Hermans; Gemma L Kelly; Margs S Brennan; Natalie L Downer; Nghi Nguyen; Johannes Wichmann; Helen M McRae; Yuqing Yang; Ben Cleary; H Rachel Lagiakos; Stephen Mieruszynski; Guido Pacini; Hannah K Vanyai; Maria I Bergamasco; Rose E May; Bethany K Davey; Kimberly J Morgan; Andrew J Sealey; Beinan Wang; Natasha Zamudio; Stephen Wilcox; Alexandra L Garnham; Bilal N Sheikh; Brandon J Aubrey; Karen Doggett; Matthew C Chung; Melanie de Silva; John Bentley; Pat Pilling; Meghan Hattarki; Olan Dolezal; Matthew L Dennis; Hendrik Falk; Bin Ren; Susan A Charman; Karen L White; Jai Rautela; Andrea Newbold; Edwin D Hawkins; Ricky W Johnstone; Nicholas D Huntington; Thomas S Peat; Joan K Heath; Andreas Strasser; Michael W Parker; Gordon K Smyth; Ian P Street; Brendon J Monahan; Anne K Voss; Tim Thomas Journal: Nature Date: 2018-08-01 Impact factor: 49.962
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Authors: Chiara Parodi; Elisabetta Di Fede; Angela Peron; Ilaria Viganò; Paolo Grazioli; Silvia Castiglioni; Richard H Finnell; Cristina Gervasini; Aglaia Vignoli; Valentina Massa Journal: Front Cell Dev Biol Date: 2021-04-20