title: Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells.
abstract: OBJECTIVE
  Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs).
  
  
  RESULTS
  We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP-1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB-MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1.
  
  
  METHODS
  Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype.
  
  
  CONCLUSIONS
  Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jin
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Hyang Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Jinbeom
authors.initials: J
authors.lastname: Heo
authors.affiliation: 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul, Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.affiliation: 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea.
authors.forename: Miyeon
authors.initials: M
authors.lastname: Kim
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Hae Yun
authors.initials: HY
authors.lastname: Nam
authors.affiliation: 6 Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology , Daejeon, Korea.
authors.forename: Gyong Hwa
authors.initials: GH
authors.lastname: Hong
authors.affiliation: 7 Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: You Sook
authors.initials: YS
authors.lastname: Cho
authors.affiliation: 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: 5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul, Korea.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Shin
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019898:Autocrine Communication; D002478:Cells, Cultured; D016922:Cellular Senescence; D018932:Chemokine CCL2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D018384:Oxidative Stress; D019899:Paracrine Communication; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D040081:Protein Array Analysis; D011485:Protein Binding; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D063150:Polycomb Repressive Complex 1; D048051:p38 Mitogen-Activated Protein Kinases