title: Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells.
abstract: Down's syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California 95817, USA [2] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California 95817, USA [3] Department of Neurology, Institute of Neurology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, China [4].
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California 95817, USA [2] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California 95817, USA [3].
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.affiliation: 1] Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [2] Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [3] Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92037, USA [4] Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Xue
authors.affiliation: Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Peterson
authors.affiliation: Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ha T
authors.initials: HT
authors.lastname: Tran
authors.affiliation: 1] Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA [2] Present address: Department of Biology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: McCann
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Mana M
authors.initials: MM
authors.lastname: Parast
authors.affiliation: 1] Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [2] Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California 95817, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.affiliation: 1] Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92037, USA [2] Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Laurent
authors.affiliation: 1] Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92037, USA [2] Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Loring
authors.affiliation: 1] Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [2] Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [3] Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92037, USA [4] Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California 95817, USA [2] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California 95817, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002470:Cell Survival; D017690:Cell Transplantation / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology*; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology* / Q000637:transplantation; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008911:Minocycline / Q000494:pharmacology; D058953:Neural Stem Cells / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000235:genetics / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D019699:Thrombospondins / Q000378:metabolism; D000099262:Thrombospondin 2
chemical_list: D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D008911:Minocycline; D052247:Nitric Oxide Synthase Type II; D064568:S100 Calcium Binding Protein beta Subunit; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2; C579160:S100B protein, human; C064658:RAG-1 protein; C496319:NOS2 protein, human