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Melatonin reverses H 2 O 2 ‐induced premature senescence in mesenchymal stem cells via the SIRT 1‐dependent pathway
Author(s) -
Zhou Long,
Chen Xi,
Liu Tao,
Gong Yihong,
Chen Sijin,
Pan Guoqing,
Cui Wenguo,
Luo ZongPing,
Pei Ming,
Yang Huilin,
He Fan
Publication year - 2015
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12250
Subject(s) - melatonin , senescence , luzindole , mesenchymal stem cell , stem cell , microbiology and biotechnology , biology , oxidative stress , endocrinology , medicine , chemistry , melatonin receptor
Mesenchymal stem cells ( MSC s) 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 MSC s against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSC s from premature senescence induced by hydrogen peroxide (H 2 O 2 ) via the silent information regulator type 1 ( SIRT 1)‐dependent pathway. In response to H 2 O 2 at a sublethal concentration of 200 μ m , human bone marrow‐derived MSC s ( BM ‐ MSC s) underwent growth arrest and cellular senescence. Treatment with melatonin before H 2 O 2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H 2 O 2 exposure successfully reversed the senescent phenotypes of BM ‐ MSC s 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 μ m melatonin restored the osteogenic differentiation potential of BM ‐ MSC s that was inhibited by H 2 O 2 ‐induced premature senescence. We also found that melatonin attenuated the H 2 O 2 ‐stimulated phosphorylation of p38 mitogen‐activated protein kinase, decreased expression of the senescence‐associated protein p16 INK 4 α , and increased SIRT 1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin‐mediated antisenescence effects. Inhibition of SIRT 1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed the senescence in cells through the SIRT 1‐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.