J Endocrinol. 2014 Sep 10. pii: JOE-14-0430. [Epub ahead of print]

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

He F¹, Liu X², Xiong K³, Chen S⁴, Zhou L⁵, Cui W⁶, Pan G⁷, Luo ZP⁸, Pei M⁹, Gong Y¹⁰.

Abstract

Both self-renewal and lineage-specific differentiation of mesenchymal stem cells 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 investigation was to evaluate the degree of adsorption of melatonin to natural cell-deposited ECM and the effects of this interaction on the biological functions of melatonin in human bone marrow-derived mesenchymal stem cells(BM-MSCs). The fibrillar microstructure, matrix composition, and melatonin-binding affinity of decellularized ECM were characterized. Cell-deposited ECM improved melatonin-mediated cell proliferation by 31.4%, attenuated 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 demonstrate the importance of native ECM in modulating the osteoinductive and antioxidant effects of melatonin and provide a novel platform to study 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 by the combination of ECM and melatonin can improve the design of graft substitutes for skeletal tissue engineering.