title: Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation.
abstract: Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-κB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-α secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-α in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy.
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.|Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, US.|Advanced Industrial Technology Research Institute, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zijiang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, US.
authors.forename: John
authors.initials: J
authors.lastname: Concannon
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.
authors.forename: Kelvin S
authors.initials: KS
authors.lastname: Ng
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, US.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Seyb
authors.affiliation: Regenerative Bioscience Center, Department of Animal and Dairy Science, and College of Engineering, University of Georgia, Athens, GA, US.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Mortensen
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.|Department of Chemical Engineering, Siddaganga Institute of Technology, Tumkur, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Ranganath
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.
authors.forename: Fangqi
authors.initials: F
authors.lastname: Gu
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.
authors.forename: Oren
authors.initials: O
authors.lastname: Levy
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Tong
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.
authors.forename: Keir
authors.initials: K
authors.lastname: Martyn
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center and Chao Family Comprehensive Cancer Center, Department of Biomedical Engineering, and Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA, US.
authors.forename: Weian
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, US.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, US.
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.affiliation: Harvard-MIT Health Sciences and Technology, Cambridge, MA, US.|Department of Medicine, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US.|Harvard Stem Cell Institute, Cambridge, MA, US.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Karp
mesh_terms: D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000276:immunology; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008403:Mass Screening; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D054852:Small Molecule Libraries
chemical_list: D044182:Benzylisoquinolines; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D054852:Small Molecule Libraries; C009438:tetrandrine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2