title: Extracellular matrix modulates the biological effects of melatonin in mesenchymal stem cells.
abstract: 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.
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA fanhe@suda.edu.cn gongyih@mail.sysu.edu.cn.
authors.forename: Fan
authors.initials: F
authors.lastname: He
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Xiong
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Sijin
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Zhou
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Wenguo
authors.initials: W
authors.lastname: Cui
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Pan
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Zong-Ping
authors.initials: ZP
authors.lastname: Luo
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Pei
authors.affiliation: School of EngineeringSun Yat-sen University, No. 132 East Waihuan Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, ChinaOrthopaedic InstituteSoochow University, No. 708 Renmin Road, Suzhou, Jiangsu 215007, ChinaDepartment of OrthopaedicsThe First Affiliated Hospital of Soochow University, Suzhou 215006, ChinaNanfang HospitalSouthern Medical University, Guangzhou 510515, ChinaStem Cell and Tissue Engineering LaboratoryDepartment of Orthopaedics, West Virginia University, Morgantown, West Virginia 26506, USA fanhe@suda.edu.cn gongyih@mail.sysu.edu.cn.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Gong
mesh_terms: D065966:Absorption, Physicochemical; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008550:Melatonin / Q000493:pharmacokinetics / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D008550:Melatonin
keywords: decellularized extracellular matrix; melatonin; mesenchymal stem cells; superoxide dismutase