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

Chen C, Jiang P, Xue H, Peterson SE, Tran HT, McCann AE, Parast MM, Li S, Pleasure DE, Laurent LC, Loring JF, Liu Y, Deng W - Nat Commun (2014)

Bottom Line: DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules.Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo.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.

View Article: PubMed Central - PubMed

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].

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.

No MeSH data available.


Related in: MedlinePlus

Gene expression analysis of DS and control astroglia.(a) Dendrogram showing that two control astroglia (Cont 1 and 2) andtwo DS astroglia (DS 1 and 2) cluster closer to each other, respectively.(b–d) Heatmaps focusing on gene transcriptsencoding antioxidants and key factors in the reactive oxidative stress(b), and factors secreted by astroglia that have roles in synapseformation (c), and neurogenesis and maturation of neurons (d).High expressions relative to mean are coloured red. Low expressions arecoloured green.
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f6: Gene expression analysis of DS and control astroglia.(a) Dendrogram showing that two control astroglia (Cont 1 and 2) andtwo DS astroglia (DS 1 and 2) cluster closer to each other, respectively.(b–d) Heatmaps focusing on gene transcriptsencoding antioxidants and key factors in the reactive oxidative stress(b), and factors secreted by astroglia that have roles in synapseformation (c), and neurogenesis and maturation of neurons (d).High expressions relative to mean are coloured red. Low expressions arecoloured green.

Mentions: Differentiation of astroglia in high purity allows us to reliably compare thegene expression profiles of DS and control astroglia. We performed global geneexpression microarray to further explore the possible mechanisms underlying theeffects of DS astroglia on NPCs and neurons. As shown in Fig.6a, the dendrogram demonstrated that two control astroglia and two DSastroglia clustered closer to each other, respectively, indicating that they hadsimilar biological properties within the same group, while the gene expressionof DS astroglia with trisomy 21 was distinct from that of control astroglia.Consistent with the qPCR results, NFE2L2 gene transcript was expressed at a muchhigher level in control astroglia than in DS astroglia from microarray analysis(Fig. 6b). However, the other genes involved in theresponse to oxidative stress were expressed higher in DS astroglia (for example,GPX and PRX gene families), indicating the compensatoryresponses to the oxidative stress (for example, ROS production in Fig. 2b) that observed in DS astroglia. We then focused on analysingthe gene transcripts encoding secreted factors, including factors that promotesynaptogenesis (for example, glypicans (GPCs), TSPs and neuroligin; Fig. 6c), and factors that promote differentiation andmaturation of neurons (for example, BDNF, BMPs, fibroblast growth factors (FGFs) and Wntligands; Fig. 6d). The detailed information of these genesand the fold changes were shown in Supplementary Table 2. Notably, heatmaps in Fig.6c,d showed the higher gene expression level for TSP-1, TSP-2 and GPC6, consistent with the qPCRresults (Fig. 2a). Although both DS and control astrogliahighly expressed the genes encoding synaptogenic factors, the differentialexpression profile may underlie the deficit of DS astroglia in promotingsynaptogenesis, particularly the lower expression of the factors that stronglypromote synaptogenesis in DS astroglia, such as BDNF41, APOE4243,TSP-1 and TSP-2 (refs 29, 44), and GPC6 (ref. 31). We also noticed that DS astroglia expressed higher levels ofgenes encoding BMPs (for example, BMP5, 6, 7 and 11) and FGFs (for example, FGF 11, 12, 13, 18 and 9), which maylargely contribute to the effect of DS astroglia on impaired neurogenesis fromNPCs because BMPs promote astroglia differentiation both in vitro45 and in vivo46, and the extra production ofFGFs may act as mitogens, preventing NPCs from differentiating to neurons.


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

Chen C, Jiang P, Xue H, Peterson SE, Tran HT, McCann AE, Parast MM, Li S, Pleasure DE, Laurent LC, Loring JF, Liu Y, Deng W - Nat Commun (2014)

Gene expression analysis of DS and control astroglia.(a) Dendrogram showing that two control astroglia (Cont 1 and 2) andtwo DS astroglia (DS 1 and 2) cluster closer to each other, respectively.(b–d) Heatmaps focusing on gene transcriptsencoding antioxidants and key factors in the reactive oxidative stress(b), and factors secreted by astroglia that have roles in synapseformation (c), and neurogenesis and maturation of neurons (d).High expressions relative to mean are coloured red. Low expressions arecoloured green.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109022&req=5

f6: Gene expression analysis of DS and control astroglia.(a) Dendrogram showing that two control astroglia (Cont 1 and 2) andtwo DS astroglia (DS 1 and 2) cluster closer to each other, respectively.(b–d) Heatmaps focusing on gene transcriptsencoding antioxidants and key factors in the reactive oxidative stress(b), and factors secreted by astroglia that have roles in synapseformation (c), and neurogenesis and maturation of neurons (d).High expressions relative to mean are coloured red. Low expressions arecoloured green.
Mentions: Differentiation of astroglia in high purity allows us to reliably compare thegene expression profiles of DS and control astroglia. We performed global geneexpression microarray to further explore the possible mechanisms underlying theeffects of DS astroglia on NPCs and neurons. As shown in Fig.6a, the dendrogram demonstrated that two control astroglia and two DSastroglia clustered closer to each other, respectively, indicating that they hadsimilar biological properties within the same group, while the gene expressionof DS astroglia with trisomy 21 was distinct from that of control astroglia.Consistent with the qPCR results, NFE2L2 gene transcript was expressed at a muchhigher level in control astroglia than in DS astroglia from microarray analysis(Fig. 6b). However, the other genes involved in theresponse to oxidative stress were expressed higher in DS astroglia (for example,GPX and PRX gene families), indicating the compensatoryresponses to the oxidative stress (for example, ROS production in Fig. 2b) that observed in DS astroglia. We then focused on analysingthe gene transcripts encoding secreted factors, including factors that promotesynaptogenesis (for example, glypicans (GPCs), TSPs and neuroligin; Fig. 6c), and factors that promote differentiation andmaturation of neurons (for example, BDNF, BMPs, fibroblast growth factors (FGFs) and Wntligands; Fig. 6d). The detailed information of these genesand the fold changes were shown in Supplementary Table 2. Notably, heatmaps in Fig.6c,d showed the higher gene expression level for TSP-1, TSP-2 and GPC6, consistent with the qPCRresults (Fig. 2a). Although both DS and control astrogliahighly expressed the genes encoding synaptogenic factors, the differentialexpression profile may underlie the deficit of DS astroglia in promotingsynaptogenesis, particularly the lower expression of the factors that stronglypromote synaptogenesis in DS astroglia, such as BDNF41, APOE4243,TSP-1 and TSP-2 (refs 29, 44), and GPC6 (ref. 31). We also noticed that DS astroglia expressed higher levels ofgenes encoding BMPs (for example, BMP5, 6, 7 and 11) and FGFs (for example, FGF 11, 12, 13, 18 and 9), which maylargely contribute to the effect of DS astroglia on impaired neurogenesis fromNPCs because BMPs promote astroglia differentiation both in vitro45 and in vivo46, and the extra production ofFGFs may act as mitogens, preventing NPCs from differentiating to neurons.

Bottom Line: DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules.Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo.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.

View Article: PubMed Central - PubMed

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].

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.

No MeSH data available.


Related in: MedlinePlus