Extracellular matrix modulates the biological effects of melatonin in mesenchymal stem cells

    1. Yihong Gong1
    1. 1School of Engineering, Sun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China
      2Orthopaedic Institute, Soochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, China
      3Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
      4Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
      5Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA
    1. Correspondence should be addressed to F He or Y Gong; Emails: fanhe{at}suda.edu.cn or gongyih{at}mail.sysu.edu.cn


    Both self-renewal and lineage-specific differentiation of mesenchymal stem cells (MSCs) are triggered by their in vivo microenvironment including the extracellular matrix (ECM) and secreted hormones. The ECM may modulate the physiological functions of hormones by providing binding sites and by regulating downstream signaling pathways. Thus, the purpose of this study was to evaluate the degree of adsorption of melatonin to a natural cell-deposited ECM and the effects of this interaction on the biological functions of melatonin in human bone marrow-derived MSCs (BM-MSCs). The fibrillar microstructure, matrix composition, and melatonin-binding affinity of decellularized ECM were characterized. The cell-deposited ECM improved melatonin-mediated cell proliferation by 31.4%, attenuated accumulation of intracellular reactive oxygen species accumulation, and increased superoxide dismutase (SOD) mRNA and protein expression. Interaction with ECM significantly enhanced the osteogenic effects of melatonin on BM-MSCs by increasing calcium deposition by 30.5%, up-regulating osteoblast-specific gene expression and down-regulating matrix metalloproteinase (MMP) expression. The underlying mechanisms of these changes in expression may involve intracellular antioxidant enzymes, because osteoblast-specific genes were down-regulated, whereas MMP expression was up-regulated, in the presence of SOD-specific inhibitors. Collectively, our findings indicate the importance of native ECM in modulating the osteoinductive and antioxidant effects of melatonin and provide a novel platform for studying the biological actions of growth factors or hormones in a physiologically relevant microenvironment. Moreover, a better understanding of the enhancement of MSC growth and osteogenic differentiation resulting from the combination of ECM and melatonin could improve the design of graft substitutes for skeletal tissue engineering.

    • Received in final form 22 August 2014
    • Accepted 8 September 2014
    • Made available online as an Accepted Preprint 10 September 2014
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    1. J Endocrinol 223 167-180
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