Unknown,Transcriptomics,Genomics,Proteomics

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Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells: proof of principle and preliminary findings

ABSTRACT: Induced pluripotent stem cell (iPSC) technology has the potential to address the inaccessibility of the human brain by providing investigators with patient-specific neurons that can potentially be used to carry out molecular, electrophysiological and pharmacological studies {{855 Takahashi,K. 2006}}. Although iPSC technology was primarily conceived and developed as a means to bypass the use of human embryonic stem cells (hESCs) for regenerative medicine, its potential for disease modeling may prove to be equally valuable, especially for neuropsychiatric disorders. A total of 1207 genes were found to be differentially expressed using LIMMA (>2-fold, p-value <0.05), and these genes were hierarchically clustered to form 5 groups based on their expression in day 0, 10 and 32. These were subjected to bioinformatics analysis by Gene Ontogoly (GO) and Ingenuity Pathway Analysis (IPA) to determine enrichment profiles and associated disease processes. The largest cluster (cluster III), which showed increasing expression in both day 10 and day 32 neurons, was found to be enriched with genes involved in a number of neuronal pathways including neurogenesis, neuronal differentiation, axon guidance and adhesion, among others. At a p-value of 0.05, we detected 645 and 383 genes up- and down-regulated between day 0 and day 10, respectively, and 146 and 280 genes up- and down-regulated between day 10 and day 32. In total, 1207 genes were found to be differentially expressed using LIMMA, and these genes were hierarchically clustered to form 5 groups.

ORGANISM(S): Homo sapiens

SUBMITTER: Herb Lachman

PROVIDER: E-GEOD-26629 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In this study we have compared functional and molecular properties of highly purified murine induced pluripotent stem (iPS) cell- and embryonic stem (ES) cell-derived cardiomyocytes (CM). In order to obtain large amounts of purified CM, we have generated a transgenic murine iPS cell line, which expresses puromycin resistance protein N-acetyltransferase and EGFP under the control of the cardiomyocyte-specific α-myosin heavy chain promoter (alphaMHC-Puro-IRES-GFP, aPiG). We demonstrate that murine aPIG-iPS and aPIG-ES cells differentiate into spontaneously beating CM at comparable efficiencies. When selected with puromycin both cell types yielded more than 97% pure population of CMs. Both aPIG-iPS and aPIG-ES cell-derived CM express typical cardiac transcripts and structural proteins and possess similar sarcomeric organization. Action potential recordings revealed that iPS- and ES cell-derived CM respond to beta-adrenergic and muscarinic receptor modulation, express functional voltage-gated sodium, calcium and potassium channels and possess comparable current densities. Comparison of global gene expression profiles of CM generated from iPS and ES cells revealed that both cell types cluster close to each other but are highly distant to undifferentiated ES or iPS cells as well as unpurified iPS and ES cell-derived embryoid bodies (EB). Both iPS and ES cell-derived CMs express genes and functional categories typical for CM. They are enriched in genes involved in transcription and genes coding for structural proteins involved in cardiac muscle contraction and relaxation. They also express genes involved in heart and muscle developmental processes, ion export and ion binding processes and various metabolic processes for ATP synthesis. These CMs downregulate genes involved in immune response, cell cycle and cell division, thus demonstrating the CMs population is mitotically inactive. Most surface signaling pathways are also downregulated. Thus, a transgenic aPiG-iPS cell line can provide a robust supply of highly purified and functional CMs for future in vitro and in vivo studies. Seven different experimental groups were included into analysis: undifferentiated murine ES cells (1) and undifferentiated murine iPS cells (2), murine ES cell-derived embyroid bodies (3) and murine iPS cell-derived embryoid bodies at day 16 of differentiation (4), murine ES cell-derived cardiomyocytes (5) and murine iPS cell-derived cardiomyocytes (6) at day 16 of differentiation (they were generated by puromycin selection for 7 days prior to RNA isolation). Adult mouse tail tip fibroblasts (7) were used as a control for iPS cells. Total RNA samples were prepared from three independent biological replicates in groups 1-6. In group 7, single RNA probes were analyzed as three technical replicates.

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Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells: proof of principle and preliminary findings

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