Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of neurosphere-derived cell lines from patients with brain disorders

ABSTRACT: Understanding the molecular bases of neurological and psychiatric conditions is hampered by a lack of suitable patient-derived cellular models. The olfactory mucosa is a continually regenerating neural tissue that contains multipotent neural stem cells which are accessible and expandable in vitro as neurospheres. Here we demonstrate disease-specific differences in neurosphere-derived cell lines from patients with two unrelated neurological conditions. Lines derived from donors with schizophrenia exhibited significant dysregulation of neurodevelopmental pathways whereas those obtained from donors with Parkinson's disease demonstrated significant dysgregulation in mitochondrial function, oxidative stress and xenobiotic metabolism. Our model supports the hypothesis that diseases with multiple genetic and environmental risk factors are revealed in convergent cellular and molecular pathways in olfactory neurosphere-derived cells taken from patient cohorts. These patient-derived cells provide informative models that provide insights into neurobiological correlates of neurological and psychiatric disorders that may be useful for many neuropsychiatric/neurodegenerative conditions and for drug discovery

ORGANISM(S): Homo sapiens

DISEASE(S): Parkinson's disease

SUBMITTER: Nicholas Matigian

PROVIDER: E-TABM-724 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Variance of gene expression identifies altered network constraints in neurological disease.

Mar Jessica C JC Matigian Nicholas A NA Mackay-Sim Alan A Mellick George D GD Sue Carolyn M CM Silburn Peter A PA McGrath John J JJ Quackenbush John J Wells Christine A CA

PLoS genetics 20110811 8

Gene expression analysis has become a ubiquitous tool for studying a wide range of human diseases. In a typical analysis we compare distinct phenotypic groups and attempt to identify genes that are, on average, significantly different between them. Here we describe an innovative approach to the analysis of gene expression data, one that identifies differences in expression variance between groups as an informative metric of the group phenotype. We find that genes with different expression varian ...[more]

PMID: 21852951

Publication: 1/2

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Project description:Neural stem cell (NSC) transplantation replaces damaged brain cells and provides disease-modifying effects in many neurological disorders. However, there has been no efficient way to obtain autologous NSCs in patients. Given that ectopic factors can reprogram somatic cells to be pluripotent, we attempted to generate human NSC-like cells by reprograming human fibroblasts. Fibroblasts were transfected with NSC line-derived cellular extracts and grown in neurosphere culture conditions. The cells were then analyzed for NSC characteristics, including neurosphere formation, gene expression patterns, and ability to differentiate. The obtained induced neurosphere-like cells (iNS), which formed daughter neurospheres after serial passaging, expressed neural stem cell markers, and had demethylated SOX2 regulatory regions, all characteristics of human NSCs. The iNS had gene expression patterns that were a combination of the patterns of NSCs and fibroblasts, but they could be differentiated to express neuroglial markers and neuronal sodium channels. These results show for the first time that iNS can be directly generated from human fibroblasts. Further studies on their application in neurological diseases are warranted. We generated induced neural stem cells (iNS) and compared the gene expressions with control cells, which included primary human dermal fibroblast cultured in DMEM media (FB), primary human dermal fibroblast cultured in neurosphere-forming condition (FB_con), and neural stem cell line (F3). The four cell lines (iNS, FB, FB_con, and F3) showed different gene expression patterns. In detail, RNA was isolated using Trizol (Invitrogen) according to the manufacturer's instructions, and was labeled and hybridized to an Affimetrix GeneChip human gene 1.0 ST array (Affimetrix, Santa Clara, CA, USA) as described according to the manufacturer’s instructions. Data were analyzed using Expression Console software version 1.1 (Affimetrix), in which gene expression ratios were normalized by Robust Multichip Analysis according to the manufacturer’s protocol.

Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

Dataset Information

Transcription profiling of neurosphere-derived cell lines from patients with brain disorders

Publications

Variance of gene expression identifies altered network constraints in neurological disease.

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