title: Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) have been widely applied to treat various inflammatory diseases. Inflammatory cytokines can induce both apoptosis and autophagy in MSCs. However, whether autophagy plays a pro- or con-apoptosis effect on MSCs in an inflammatory microenvironment has not been clarified.
  
  
  METHODS
  We inhibited autophagy by constructing MSCs with lentivirus containing small hairpin RNA to knockdown Beclin-1 and applied these MSCs to a model of sepsis to evaluate therapeutic effect of MSCs.
  
  
  RESULTS
  Here we show that inhibition of autophagy in MSCs increases the survival rate of septic mice more than control MSCs, and autophagy promotes apoptosis of MSCs during application to septic mice. Further study demonstrated that autophagy aggravated tumor necrosis factor alpha plus interferon gamma-induced apoptosis of MSCs. Mechanically, autophagy inhibits the expression of the pro-survival gene Bcl-2 via suppressing reactive oxygen species/mitogen-activated protein kinase 1/3 pathway.
  
  
  CONCLUSIONS
  Our findings indicate that an inflammatory microenvironment-induced autophagy promotes apoptosis of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel approach to improve MSC survival during immunotherapy.
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. spdang@sibs.ac.cn.|Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China. spdang@sibs.ac.cn.|Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China. spdang@sibs.ac.cn.
authors.forename: Shipeng
authors.initials: S
authors.lastname: Dang
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. yuzhimi8660@sina.com.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. dragonet001@hotmail.com.
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. passer27@sina.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. liyantong2002@126.com.
authors.forename: Ku-Lin
authors.initials: KL
authors.lastname: Li
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. zxdl_ing@sina.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. qll900@sina.com.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Qian
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. dryangzhenyu@163.com.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. lixiaorong.dr@163.com.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Li
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China. yyzhang@sibs.ac.cn.|Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China. yyzhang@sibs.ac.cn.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China. ruxingw@aliyun.com.
authors.forename: Ru-Xing
authors.initials: RX
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D001343:Autophagy / Q000276:immunology / Q000502:physiology*; D000071186:Beclin-1; D016207:Cytokines / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism; D020935:MAP Kinase Signaling System; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000473:pathology; D055153:Stem Cell Niche / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species