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 () and Wenbin Deng ()
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Chen Chen: School of Medicine, University of California
Peng Jiang: School of Medicine, University of California
Haipeng Xue: University of Texas Health Science Center at Houston
Suzanne E. Peterson: Center for Regenerative Medicine, The Scripps Research Institute
Ha T. Tran: Center for Regenerative Medicine, The Scripps Research Institute
Anna E. McCann: Center for Regenerative Medicine, The Scripps Research Institute
Mana M. Parast: University of California, San Diego
Shenglan Li: University of Texas Health Science Center at Houston
David E. Pleasure: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children
Louise C. Laurent: University of California, San Diego
Jeanne F. Loring: University of California, San Diego
Ying Liu: University of Texas Health Science Center at Houston
Wenbin Deng: School of Medicine, University of California

Nature Communications, 2014, vol. 5, issue 1, 1-18

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5430

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