PMID- 26573462 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20181202 IS - 1557-7716 (Electronic) IS - 1523-0864 (Print) IS - 1523-0864 (Linking) VI - 24 IP - 9 DP - 2016 Mar 20 TI - Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells. PG - 471-85 LID - 10.1089/ars.2015.6359 [doi] AB - AIMS: 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. INNOVATION: 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. CONCLUSION: 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. FAU - Jin, Hye Jin AU - Jin HJ AD - 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. AD - 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea. FAU - Lee, Hyang Ju AU - Lee HJ AD - 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. FAU - Heo, Jinbeom AU - Heo J AD - 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. AD - 4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. FAU - Lim, Jisun AU - Lim J AD - 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. AD - 4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. AD - 5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul, Korea. FAU - Kim, Miyeon AU - Kim M AD - 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea. FAU - Kim, Min Kyung AU - Kim MK AD - 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. FAU - Nam, Hae Yun AU - Nam HY AD - 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. FAU - Hong, Gyong Hwa AU - Hong GH AD - 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. FAU - Cho, You Sook AU - Cho YS AD - 7 Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. FAU - Choi, Soo Jin AU - Choi SJ AD - 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea. FAU - Kim, In-Gyu AU - Kim IG AD - 5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul, Korea. FAU - Shin, Dong-Myung AU - Shin DM AD - 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. AD - 4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. FAU - Kim, Seong Who AU - Kim SW AD - 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160127 PL - United States TA - Antioxid Redox Signal JT - Antioxidants & redox signaling JID - 100888899 RN - 0 (BMI1 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Cytokines) RN - 0 (Receptors, CCR2) RN - EC 2.3.2.27 (Polycomb Repressive Complex 1) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Asthma/drug therapy/genetics/immunology/metabolism MH - Autocrine Communication MH - Cells, Cultured MH - Cellular Senescence MH - Chemokine CCL2/*metabolism MH - Cytokines/metabolism MH - Disease Models, Animal MH - Fetal Blood/cytology MH - Humans MH - Mesenchymal Stem Cells/*metabolism MH - Oxidative Stress MH - Paracrine Communication MH - Phenotype MH - Polycomb Repressive Complex 1/*metabolism MH - Protein Array Analysis MH - Protein Binding MH - Receptors, CCR2/genetics/metabolism MH - Transcription, Genetic MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC4800271 EDAT- 2015/11/18 06:00 MHDA- 2016/12/15 06:00 PMCR- 2016/03/20 CRDT- 2015/11/18 06:00 PHST- 2015/11/18 06:00 [entrez] PHST- 2015/11/18 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] PHST- 2016/03/20 00:00 [pmc-release] AID - 10.1089/ars.2015.6359 [pii] AID - 10.1089/ars.2015.6359 [doi] PST - ppublish SO - Antioxid Redox Signal. 2016 Mar 20;24(9):471-85. doi: 10.1089/ars.2015.6359. Epub 2016 Jan 27.