Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells

Chen Chen; Peng Jiang; Haipeng Xue; Suzanne E Peterson; Ha T Tran; Anna E McCann; Mana M Parast; Shenglan Li; David E Pleasure; Louise C Laurent; Jeanne F Loring; Ying Liu; Wenbin Deng

doi:10.1038/ncomms5430

Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells

Nat Commun. 2014 Jul 18:5:4430. doi: 10.1038/ncomms5430.

Authors

Chen Chen¹, Peng Jiang², Haipeng Xue³, Suzanne E Peterson⁴, Ha T Tran⁴, Anna E McCann⁵, Mana M Parast⁶, Shenglan Li⁷, David E Pleasure⁸, Louise C Laurent⁹, Jeanne F Loring⁹, Ying Liu³, Wenbin Deng¹⁰

Affiliations

¹ 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].
² 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].
³ 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.
⁴ Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
⁵ 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.
⁶ Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA.
⁷ 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.
⁸ Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California 95817, USA.
⁹ 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.
¹⁰ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / drug effects
Astrocytes / physiology*
Case-Control Studies
Cell Differentiation
Cell Survival
Cell Transplantation / methods
Culture Media, Conditioned / pharmacology
Down Syndrome / genetics
Down Syndrome / physiopathology*
Gene Expression Profiling
Glial Fibrillary Acidic Protein / metabolism
Homeodomain Proteins / genetics
Humans
Induced Pluripotent Stem Cells / physiology*
Induced Pluripotent Stem Cells / transplantation
Mice, Inbred C57BL
Mice, Mutant Strains
Minocycline / pharmacology
Neural Stem Cells / physiology
Neurons / cytology
Neurons / physiology
Nitric Oxide Synthase Type II / genetics
Nitric Oxide Synthase Type II / metabolism
S100 Calcium Binding Protein beta Subunit / genetics
S100 Calcium Binding Protein beta Subunit / metabolism
Thrombospondin 1 / metabolism
Thrombospondins / metabolism

Substances

Culture Media, Conditioned
Glial Fibrillary Acidic Protein
Homeodomain Proteins
S100 Calcium Binding Protein beta Subunit
S100B protein, human
Thrombospondin 1
Thrombospondins
thrombospondin 2
RAG-1 protein
NOS2 protein, human
Nitric Oxide Synthase Type II
Minocycline

Abstract

Publication types

MeSH terms

Substances

Grants and funding