title: Cytoprotective effect of melatonin against hypoxia/serum deprivation-induced cell death of bone marrow mesenchymal stem cells in vitro.
abstract: Bone marrow mesenchymal stem cells (MSCs) have been shown great potential for cardiac regeneration. However the therapeutic efficiency has become a major obstacle due to the poor survival of transplanted MSCs in ischemic cardiac tissue. Previous studies reported that melatonin could protect many different types of cells from apoptosis under various pathological conditions. In the present study, we demonstrated that melatonin, an endogenously secreted indoleamine had cytoprotection from hypoxia/serum deprivation (Hy/SD)-induced cell death in MSCs. We further investigated the possible mechanism and found out that melatonin attenuated (Hy/SD)-induced cell death could be via effectively reducing the generation of intracellular reactive oxygen species, an increase in the ratio of Bax/Bcl-2, loss of mitochondrial membrane potential and then activation of caspase-3 in MSCs in response to Hy/SD exposure. Furthermore, melatonin pretreatment significantly modulated the expression of phospho-P38MAPK and phospho-ERK1/2 in Hy/SD-induced MSCs and the protective effects of melatonin were partially reversed by ERK1/2 inhibitor but not p38 inhibitor, suggesting that melatonin inhibited Hy/SD-induced MSCs cell death through the MAPK signaling pathway in part. Taken together, the findings imply that melatonin could improve the survival of engrafted MSCs under hypoxia and serum deprivation condition. Our findings indicate that combination therapy with melatonin may provide therapeutic benefit for improving myocardial function after infarction.
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Fuwu
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Parasitology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Du
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Xueran
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Immunology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Qian
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, No.107, Wenhua Xi Road, Shandong, Jinan, PR China. Electronic address: lixg@sdu.edu.cn.
authors.forename: Xingang
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Shandong, Jinan, PR China. Electronic address: aijunhao@sdu.edu.cn.
authors.forename: Aijun
authors.initials: A
authors.lastname: Hao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007511:Ischemia / Q000473:pathology; D008550:Melatonin / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044967:Serum / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D008550:Melatonin
keywords: Apoptosis; CM-DCF (Pubchem CID: 77718); DAPI (Pubchem CID: 2954); DHE (Pubchem CID: 128682); ERK inhibitor PD98059 (Pubchem CID: 4713); Hypoxia/serum deprivation; JC-1 (Pubchem CID: 5492929); Melatonin; Melatonin (Pubchem CID: 896); Mesenchymal stem cell; Necrostatin-1 (Pubchem CID: 2828334); P38 inhibitor SB203580 (Pubchem CID: 176155); Propidium iodide (Pubchem CID: 104981); Thiazolyl blue tetrazolium bromide (Pubchem CID: 64965)