title: Melatonin reverses H2 O2 -induced premature senescence in mesenchymal stem cells via the SIRT1-dependent pathway.
abstract: Mesenchymal stem cells (MSCs) represent an attractive source for stem cell-based regenerative therapy, but they are vulnerable to oxidative stress-induced premature senescence in pathological conditions. We previously reported antioxidant and antiarthritic effects of melatonin on MSCs against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSCs from premature senescence induced by hydrogen peroxide (H2 O2 ) via the silent information regulator type 1 (SIRT1)-dependent pathway. In response to H2 O2 at a sublethal concentration of 200 μm, human bone marrow-derived MSCs (BM-MSCs) underwent growth arrest and cellular senescence. Treatment with melatonin before H2 O2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H2 O2 exposure successfully reversed the senescent phenotypes of BM-MSCs in a dose-dependent manner. This result was made evident by improved cell proliferation, decreased senescence-associated β-galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 μm melatonin restored the osteogenic differentiation potential of BM-MSCs that was inhibited by H2 O2 -induced premature senescence. We also found that melatonin attenuated the H2 O2 -stimulated phosphorylation of p38 mitogen-activated protein kinase, decreased expression of the senescence-associated protein p16(INK) (4α) , and increased SIRT1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin-mediated antisenescence effects. Inhibition of SIRT1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed the senescence in cells through the SIRT1-dependent pathway. Together, these findings lay new ground for understanding oxidative stress-induced premature senescence and open perspectives for therapeutic applications of melatonin in stem cell-based regenerative medicine.
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.|School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Sijin
authors.initials: S
authors.lastname: Chen
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Pan
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Wenguo
authors.initials: W
authors.lastname: Cui
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Zong-Ping
authors.initials: ZP
authors.lastname: Luo
authors.affiliation: Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, Morgantown, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Pei
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Orthopaedic Institute, Medical College, Soochow University, Suzhou, China.|Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Fan
authors.initials: F
authors.lastname: He
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D016922:Cellular Senescence / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008550:Melatonin / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology*; D009284:Naphthols / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001549:Benzamides; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009284:Naphthols; C439060:sirtinol; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D008550:Melatonin
keywords: SIRT1; hydrogen peroxide; melatonin; mesenchymal stem cells; senescence