title: Synergistic protection of N-acetylcysteine and ascorbic acid 2-phosphate on human mesenchymal stem cells against mitoptosis, necroptosis and apoptosis.
abstract: Human mesenchymal stem cells (hMSCs) contribute to ischemic tissue repair, regeneration, and possess ability to self-renew. However, poor viability of transplanted hMSCs within ischemic tissues has limited its therapeutic efficiency. Therefore, it is urgent to explore new method to improve the viability of the grafted cells. By using a systematic analysis, we reveal the mechanism of synergistic protection of N-acetylcysteine (NAC) and ascorbic acid 2-phosphate (AAP) on hMSCs that were under H2O2-induced oxidative stress. The combined treatment of NAC and AAP (NAC/AAP) reduces reactive oxygen species (ROS) generation, stabilizes mitochondrial membrane potential and decreases mitochondrial fission/fragmentation due to oxidative stress. Mitochondrial fission/fragmentation is a major prologue of mitoptosis. NAC/AAP prevents apoptotic cell death via decreasing the activation of BAX, increasing the expression of BCL2, and reducing cytochrome c release from mitochondria that might lead to the activation of caspase cascade. Stabilization of mitochondria also prevents the release of AIF, and its nuclear translocation which may activate necroptosis via H2AX pathway. The decreasing of mitoptosis is further studied by MicroP image analysis, and is associated with decreased activation of Drp1. In conclusion, NAC/AAP protects mitochondria from H2O2-induced oxidative stress and rescues hMSCs from mitoptosis, necroptosis and apoptosis.
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Li
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Li-Yi
authors.initials: LY
authors.lastname: Sun
authors.affiliation: 1] Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan [2] Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Cheng-Yoong
authors.initials: CY
authors.lastname: Pang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004357:Drug Synergism; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; C468783:H2AX protein, human; D006657:Histones; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C011669:ascorbate-2-phosphate; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D001205:Ascorbic Acid; D000111:Acetylcysteine