Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells
Authors: Anna E McCann
Mana M Parast
Ha T Tran
Wenbin Deng
Shenglan Li
Jeanne F Loring
David E Pleasure
Haipeng Xue
Suzanne E Peterson
Chen Chen
Peng Jiang
Ying Liu
Louise C Laurent
Journal: Nature Communications (2014)
Discipline: Multidisciplinary
Keywords: Down's syndrome; trisomy; intellectual disability; induced pluripotent stem cells; astrocytes
Affiliations: 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]., 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]., 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., Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA., 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., Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA., 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., Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California 95817, USA., 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., 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. 

Retracted: No

PubPeer comments:
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