Olfactory neuroepithelium-derived neural progenitor cells as a model system for investigating the molecular mechanisms of neuropsychiatric disorders

Evgrafov, Oleg V.; Wrobel, Bozena; Kang, Xin; Simpson, George M.; Malaspina, Dolores; Knowles, James A.

doi:10.1097/ypg.0b013e328341a2f0

Cited by 21 publications

(35 citation statements)

References 55 publications

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“…Several lines of evidence point to neurodevelopment as playing a primary role in etiology of the disease (Weinberger, 1987; Raedler et al, 1998; Lewis and Levitt, 2002). To elucidate neurodevelopmental aspects of SCZ mechanisms we studied gene expression profiles in CNON cells derived from SCZ patients and healthy individuals, a suitable experimental model to analyze the neurodevelopment processes (Evgrafov et al, 2006, 2017; Wrobel et al, 2013). SCZ-related genes that differ between SCZ and control groups in the mean expression levels have been identified from these data (Evgrafov et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The details of biopsy and cell cultivation were described previously (Evgrafov et al, 2006; Wrobel et al, 2013). RNA libraries extracted from cells were prepared and sequenced on HiSeq2000 (Illumina) as previously described (Evgrafov et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

“…It allows the investigation of pathways and molecular networks affected by SCZ. The difficulties in studying gene expression in human patients with neurological disease has led to the adoption of relevant cellular models (Evgrafov et al, 2006) to facilitate understanding of cellular phenotypes. While post-mortem brain tissue samples are used to study gene expression changes in neurological diseases like SCZ (e.g., Chen et al, 2013; Lanz et al, 2015; Hu et al, 2016), these are comprised of terminally differentiated neurons and glial cells of an adult brain which has been subjected to many different environmental conditions.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Igolkina

Armoskus

Newman

et al. 2018

Front. Mol. Neurosci.

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Schizophrenia (SCZ) is a psychiatric disorder of unknown etiology. There is evidence suggesting that aberrations in neurodevelopment are a significant attribute of schizophrenia pathogenesis and progression. To identify biologically relevant molecular abnormalities affecting neurodevelopment in SCZ we used cultured neural progenitor cells derived from olfactory neuroepithelium (CNON cells). Here, we tested the hypothesis that variance in gene expression differs between individuals from SCZ and control groups. In CNON cells, variance in gene expression was significantly higher in SCZ samples in comparison with control samples. Variance in gene expression was enriched in five molecular pathways: serine biosynthesis, PI3K-Akt, MAPK, neurotrophin and focal adhesion. More than 14% of variance in disease status was explained within the logistic regression model (C-value = 0.70) by predictors accounting for gene expression in 69 genes from these five pathways. Structural equation modeling (SEM) was applied to explore how the structure of these five pathways was altered between SCZ patients and controls. Four out of five pathways showed differences in the estimated relationships among genes: between KRAS and NF1, and KRAS and SOS1 in the MAPK pathway; between PSPH and SHMT2 in serine biosynthesis; between AKT3 and TSC2 in the PI3K-Akt signaling pathway; and between CRK and RAPGEF1 in the focal adhesion pathway. Our analysis provides evidence that variance in gene expression is an important characteristic of SCZ, and SEM is a promising method for uncovering altered relationships between specific genes thus suggesting affected gene regulation associated with the disease. We identified altered gene-gene interactions in pathways enriched for genes with increased variance in expression in SCZ. These pathways and loci were previously implicated in SCZ, providing further support for the hypothesis that gene expression variance plays important role in the etiology of SCZ.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Igolkina

Armoskus

Newman

et al. 2018

Front. Mol. Neurosci.

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“…We generated a NOME-seq library using CNON (Cultured Neuronal cells derived from Olfactory Neuroepithelium) cells [26] from patient sample 45 as part of the PsychENCODE project (https://www.synapse.org/#iSynapse:syn4921369/wiki/235539) [27] using 100bp paired-end sequencing with the Illumina Hi-Seq 2500. To compare NDRs to regulatory elements defined by the H3K4me3 promoter mark, the H3K27ac enhancer mark, and CTCF binding sites, we also generated ChIP-seq libraries with proper antibodies using our previously published protocols for histones and site-specific DNA binding factors [10,28].…”

Section: Methodsmentioning

confidence: 99%

Defining Regulatory Elements in the Human Genome Using Nucleosome Occupancy and Methylome Sequencing (NOMe-Seq)

Rhie

Schreiner

Farnham

2018

Methods in Molecular Biology

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NOMe-seq (nucleosome occupancy and methylome sequencing) identifies nucleosome- depleted regions that correspond to promoters, enhancers, and insulators. The NOMe-seq method is based on the treatment of chromatin with the M.CviPI methyltransferase, which methylates GpC dinucleotides that are not protected by nucleosomes or other proteins that are tightly bound to the chromatin (GpCm does not occur in the human genome and therefore there is no endogenous background of GpCm). Following bisulfite treatment of the M.CviPI-methylated chromatin (which converts unmethylated Cs to Ts and thus allows the distinction of GpC from GpCm) and subsequent genomic sequencing, nucleosome-depleted regions can be ascertained on a genome-wide scale. The bisulfite treatment also allows the distinction of CpG from CmpG (most endogenous methylation occurs at CpG dinucleotides) and thus the endogenous methylation status of the genome can also be obtained in the same sequencing reaction. Importantly, open chromatin is expected to have high levels of GpCm but low levels of CmpG; thus, each of the two separate methylation analyses serve as independent (but opposite) measures which provide matching chromatin designations for each regulatory element.

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“…This capacity of regeneration candidates the stem cells of olfactory epithelium as an efficient source for treatment of neurodegenerative disorders of CNS (Evgrafov et al, 2011;Mackay-Sim, 2012). The neural stem cells of the olfactory epithelium were previously isolated and characterized (Calof et al, 2002;Hahn et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Olfactory Epithelium as an Infinitive Source of Neural Stem Cells for Derivation of Inner Ear Hair Cells

et al. 2017

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SUMMARY:Surgical techniques for treatment of sensory neural hearing loss (SNHL) have unpredictable outcomes and in recent years cell therapy investigated for treatment of SNHL. Olfactory epithelium proceed neurogenesis during life time and provide an easily accessible source of neural stem cells. So the aim of this study was isolating neural stem cells from olfactory epithelium of rat and differentiation of these cells into hair cells of inner ear in vitro. The epithelium tissue of olfactory mucosa of rats were removed and digested by collagenase H. The digested tissue was cultured in flasks in suspension forms to create spheres. Spheres were passaged and from passage 2 spheres selected for differentiation. At this stage cells of spheres isolated from each other and placed in flask containing defined differentiation medium. Cells at this stage cultured in adhesive form. Immunohistochemistry and RT-PCR were used for neural stem cells and hair cells identification. Spheres formed from olfactory epithelium culture and immunohistochemistry revealed that cells of spheres from passage one and two expressed the neural stem cells markers. After culture of isolated cells in differentiation medium, the morphology of cells begun to change. The cells presented neural cells projections and after 10 days the projections elongated more and interact to each other in multi layers. RT-PCR and immunohistochemistry revealed that differentiated cells expressed hair cells specific genes. In this study we showed that neural stem cells of olfactory epithelium can differentiate into hair cells of inner ear and therefore can be used for treatment of SNHL.

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Olfactory neuroepithelium-derived neural progenitor cells as a model system for investigating the molecular mechanisms of neuropsychiatric disorders

Cited by 21 publications

References 55 publications

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Defining Regulatory Elements in the Human Genome Using Nucleosome Occupancy and Methylome Sequencing (NOMe-Seq)

Olfactory Epithelium as an Infinitive Source of Neural Stem Cells for Derivation of Inner Ear Hair Cells

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