Melatonin reverses H2O2‐induced premature senescence in mesenchymal stem cells via the SIRT1‐dependent pathway. Issue 2 (7th July 2015)

• Record Type: Journal Article
• Authors: Zhou, Long; Chen, Xi; Liu, Tao; Gong, Yihong; Chen, Sijin; Pan, Guoqing; Cui, Wenguo; Luo, Zong‐Ping; Pei, Ming; Yang, Huilin; He, Fan
• Is Part Of: Journal of pineal research. Volume 59:Issue 2(2015)
• Page Start: 190
• Page End: 205
• Publication Date: 2015-07-07
• Subjects: Pineal gland -- Periodicals; Pineal Gland -- Periodicals; Épiphyse (Glande); Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 612.492
• DOI: 10.1111/jpi.12250
• Languages: English
• ISSNs: 0742-3098

Abstract

<abstract abstract-type="main" id="jpi12250-abs-0001"> <title>Abstract</title> <p>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 (H<sub>2</sub>O<sub>2</sub>) via the silent information regulator type 1 (SIRT1)‐dependent pathway. In response to H<sub>2</sub>O<sub>2</sub> at a sublethal concentration of 200 <italic>μ</italic><sc>m</sc>, human bone marrow‐derived MSCs (BM‐MSCs) underwent growth arrest and cellular senescence. Treatment with melatonin before H<sub>2</sub>O<sub>2</sub> exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H<sub>2</sub>O<sub>2</sub> 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 <italic>β</italic>‐galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 <italic>μ</italic><sc>m</sc> melatonin restored the osteogenic differentiation potential of BM‐MSCs that was inhibited by H<sub>2</sub>O<sub>2</sub>‐induced premature senescence. We also found that melatonin attenuated the H<sub>2</sub>O<sub>2</sub>‐stimulated phosphorylation of p38 mitogen‐activated protein kinase, decreased expression of the senescence‐associated protein p16<sup>INK</sup><sup>4<italic>α</italic></sup>, 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.</p> </abstract>