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Generation of Human Neurons and Oligodendrocytes from Pluripotent Stem Cells for Modeling Neuron-Oligodendrocyte Interactions. Journal of visualized experiments : JoVE Assetta, B., Tang, C., Bian, J., O'Rourke, R., Connolly, K., Brickler, T., Chetty, S., Huang, Y. A. 2020
Abstract

In Alzheimer's disease (AD) and other neurodegenerative disorders, oligodendroglial failure is a common early pathological feature, but how it contributes to disease development and progression, particularly in the gray matter of the brain, remains largely unknown. The dysfunction of oligodendrocyte lineage cells is hallmarked by deficiencies in myelination and impaired self-renewal of oligodendrocyte precursor cells (OPCs). These two defects are caused at least in part by the disruption of interactions between neuron and oligodendrocytes along the buildup of pathology. OPCs give rise to myelinating oligodendrocytes during CNS development. In the mature brain cortex, OPCs are the major proliferative cells (comprising ~5% of total brain cells) and control new myelin formation in a neural activity-dependent manner. Such neuron-to-oligodendrocyte communications are significantly understudied, especially in the context of neurodegenerative conditions such as AD, due to the lack of appropriate tools. In recent years, our group and others have made significant progress to improve currently available protocols to generate functional neurons and oligodendrocytes individually from human pluripotent stem cells. In this manuscript, we describe our optimized procedures, including the establishment of a co-culture system to model the neuron-oligodendrocyte connections. Our illustrative results suggest an unexpected contribution from OPCs/oligodendrocytes to the brain amyloidosis and synapse integrity and highlight the utility of this methodology for AD research. This reductionist approach is a powerful tool to dissect the specific hetero-cellular interactions out of the inherent complexity inside the brain. The protocols we describe here are expected to facilitate future studies on oligodendroglial defects in the pathogenesis of neurodegeneration.

View details for DOI 10.3791/61778

View details for PubMedID 33226027
Variations and expression features of CYP2D6 contribute to schizophrenia risk. Molecular psychiatry Ma, L., Shcherbina, A., Chetty, S. 2020
Abstract

Genome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown. Here, we analyze 1497 RNA-seq data in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we colocalize eGene and eJunction with SCZ GWAS using SMR and fine mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causal variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways. We identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1, and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in eGene and eJunction. In-depth examination of the CYP2D6 region revealed that a nonsynonymous single nucleotide variant rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and other functional SNPs in high linkage disequilibrium with rs16947 (r2?=?0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed that CYP2D6 is significantly involved in drug metabolism of codeine, tamoxifen, and citalopram. Our study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.

View details for DOI 10.1038/s41380-020-0675-y

View details for PubMedID 32047265
Cell cycle dynamics of human pluripotent stem cells primed for differentiation. Stem cells (Dayton, Ohio) Shcherbina, A., Li, J., Narayanan, C., Greenleaf, W., Kundaje, A., Chetty, S. 2019
Abstract

Understanding the molecular properties of the cell cycle of human pluripotent stem cells (hPSCs) is critical for effectively promoting differentiation. Here, we use the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) system adapted into hPSCs and perform RNA-sequencing on cell cycle sorted hPSCs primed and unprimed for differentiation. Gene expression patterns of signaling factors and developmental regulators change in a cell cycle-specific manner in cells primed for differentiation without altering genes associated with pluripotency. Furthermore, we identify an important role for PI3K signaling in regulating the early transitory states of hPSCs toward differentiation. SIGNIFICANCE STATEMENT: Generating differentiated cell types from human pluripotent stem cells (hPSCs) holds great therapeutic promise, but has proven to be challenging in practice. The cell cycle may play an important role in enhancing the differentiation potential of hPSCs. Here, the authors track and isolate hPSCs from different phases of the cell cycle and perform RNA-sequencing. The data show that gene expression patterns of signaling factors and developmental regulators change in a cell cycle-specific manner as hPSCs transition toward differentiation and highlight an important role for PI3K signaling in regulating these early transitory states. � AlphaMed Press 2019.

View details for DOI 10.1002/stem.3041

View details for PubMedID 31135093
Overexpression of CD47 is associated with brain overgrowth in 16p11.2 deletion syndrome bioRxiv Li, J., Brickler, T., Banuelos, A., Marjon, K., Bian, J., Narayanan, C., Weissman, I. L., Chetty, S. 2019
View details for DOI 10.1101/808022
Transient treatment of human pluripotent stem cells with DMSO to promote differentiation JoVE Sambo, D., Li, J., Brickler, T., Chetty, S. 2019
View details for DOI 10.3791/59833
A transient DMSO treatment increases the differentiation potential of human pluripotent stem cells through the Rb family. PloS one Li, J., Narayanan, C., Bian, J., Sambo, D., Brickler, T., Zhang, W., Chetty, S. 2018; 13 (12): e0208110
Abstract

The propensity for differentiation varies substantially across human pluripotent stem cell (hPSC) lines, greatly restricting the use of hPSCs for cell replacement therapy or disease modeling. Here, we investigate the underlying mechanisms and demonstrate that activation of the retinoblastoma (Rb) pathway in a transient manner is important for differentiation. In prior work, we demonstrated that pre-treating hPSCs with dimethylsulfoxide (DMSO) before directed differentiation enhanced differentiation potential across all three germ layers. Here, we show that exposure to DMSO improves the efficiency of hPSC differentiation through Rb and by repressing downstream E2F-target genes. While transient inactivation of the Rb family members (including Rb, p107, and p130) suppresses DMSO's capacity to enhance differentiation across all germ layers, transient expression of a constitutively active (non-phosphorylatable) form of Rb increases the differentiation efficiency similar to DMSO. Inhibition of downstream targets of Rb, such as E2F signaling, also promotes differentiation of hPSCs. More generally, we demonstrate that the duration of Rb activation plays an important role in regulating differentiation capacity.

View details for PubMedID 30540809
A qPCRCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells NATURE BIOTECHNOLOGY Tsankov, A. M., Akopian, V., Pop, R., Chetty, S., Gifford, C. A., Daheron, L., Tsankova, N. M., Meissner, A. 2015; 33 (11): 1182-U117
Abstract

Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We previously described an assay called ScoreCard that used gene expression signatures to quantify differentiation efficiency. Here we report an improved version of the assay based on qPCR that enables faster, more quantitative assessment of functional pluripotency. We provide an in-depth characterization of the revised signature panel (commercially available as the TaqMan hPSC Scorecard Assay) through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We further show that the improved ScoreCard enables a wider range of applications, such as screening of small molecules, genetic perturbations and assessment of culture conditions. Our approach can be extended beyond stem cell applications to characterize and assess the utility of other cell types and lineages.

View details for DOI 10.1038/nbt.3387

View details for Web of Science ID 000364916000026

View details for PubMedID 26501952

View details for PubMedCentralID PMC4636964
A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation JOURNAL OF CELL BIOLOGY Chetty, S., Engquist, E. N., Mehanna, E., Lui, K. O., Tsankov, A. M., Melton, D. A. 2015; 210 (7): 1257-1268
Abstract

Driving human pluripotent stem cells (hPSCs) into specific lineages is an inefficient and challenging process. We show that a potent Src inhibitor, PP1, regulates expression of genes involved in the G1 to S phase transition of the cell cycle, activates proteins in the retinoblastoma family, and subsequently increases the differentiation propensities of hPSCs into all three germ layers. We further demonstrate that genetic suppression of Src regulates the activity of the retinoblastoma protein and enhances the differentiation potential of hPSCs across all germ layers. These positive effects extend beyond the initial germ layer specification and enable efficient differentiation at subsequent stages of differentiation.

View details for DOI 10.1083/jcb.201502035

View details for Web of Science ID 000362624000019

View details for PubMedID 26416968
Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus MOLECULAR PSYCHIATRY Chetty, S., Friedman, A. R., Taravosh-Lahn, K., Kirby, E. D., Mirescu, C., Guo, F., Krupik, D., Nicholas, A., Geraghty, C., Krishnamurthy, A., Tsai, M., Covarrubias, D., Wong, A. T., Francis, D. D., Sapolsky, R. M., Palmer, T. D., PLEASURE, D., Kaufer, D. 2014; 19 (12): 1275-1283
Abstract

Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

View details for DOI 10.1038/mp.2013.190

View details for PubMedID 24514565
A simple tool to improve pluripotent stem cell differentiation NATURE METHODS Chetty, S., Pagliuca, F. W., Honore, C., Kweudjeu, A., Rezania, A., Melton, D. A. 2013; 10 (6): 553-?
Abstract

We describe a method to help overcome restrictions on the differentiation propensities of human pluripotent stem cells. Culturing pluripotent stem cells in dimethylsulfoxide (DMSO) activates the retinoblastoma protein, increases the proportion of cells in the early G1 phase of the cell cycle and, in more than 25 embryonic and induced pluripotent stem cell lines, improves directed differentiation into multiple lineages. DMSO treatment also improves differentiation into terminal cell types in several cell lines.

View details for DOI 10.1038/NMETH.2442

View details for Web of Science ID 000319668700026

View details for PubMedID 23584186
Altered prefrontal function with aging: Insights into age-associated performance decline BRAIN RESEARCH Solbakk, A., Alpert, G. F., Furst, A. J., Hale, L. A., Oga, T., Chetty, S., Pickard, N., Knight, R. T. 2008; 1232: 30-47
Abstract

We examined the effects of aging on visuo-spatial attention. Participants performed a bi-field visual selective attention task consisting of infrequent target and task-irrelevant novel stimuli randomly embedded among repeated standards in either attended or unattended visual fields. Blood oxygenation level dependent (BOLD) responses to the different classes of stimuli were measured using functional magnetic resonance imaging. The older group had slower reaction times to targets, and committed more false alarms but had comparable detection accuracy to young controls. Attended target and novel stimuli activated comparable widely distributed attention networks, including anterior and posterior association cortex, in both groups. The older group had reduced spatial extent of activation in several regions, including prefrontal, basal ganglia, and visual processing areas. In particular, the anterior cingulate and superior frontal gyrus showed more restricted activation in older compared with young adults across all attentional conditions and stimulus categories. The spatial extent of activations correlated with task performance in both age groups, but the regional pattern of association between hemodynamic responses and behavior differed between the groups. Whereas the young subjects relied on posterior regions, the older subjects engaged frontal areas. The results indicate that aging alters the functioning of neural networks subserving visual attention, and that these changes are related to cognitive performance.

View details for DOI 10.1016/j.brainres.2008.07.060

View details for Web of Science ID 000260196900004

View details for PubMedID 18691562
C-11-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration NEUROLOGY Rabinovici, G. D., Furst, A. J., O'Neil, J. P., Racine, C. A., Mormino, E. C., Baker, S. L., Chetty, S., Patel, P., Pagliaro, T. A., Klunk, W. E., Mathis, C. A., Rosen, H. J., Miller, B. L., Jagust, W. J. 2007; 68 (15): 1205-1212
Abstract

The PET tracer (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) specifically binds fibrillar amyloid-beta (Abeta) plaques and can be detected in Alzheimer disease (AD). We hypothesized that PET imaging with (11)C-PIB would discriminate AD from frontotemporal lobar degeneration (FTLD), a non-Abeta dementia.Patients meeting research criteria for AD (n = 7) or FTLD (n = 12) and cognitively normal controls (n = 8) underwent PET imaging with (11)C-PIB (patients and controls) and (18)F-fluorodeoxyglucose ((18)F-FDG) (patients only). (11)C-PIB whole brain and region of interest (ROI) distribution volume ratios (DVR) were calculated using Logan graphical analysis with cerebellum as a reference region. DVR images were visually rated by a blinded investigator as positive or negative for cortical (11)C-PIB, and summed (18)F-FDG images were rated as consistent with AD or FTLD.All patients with AD (7/7) had positive (11)C-PIB scans by visual inspection, while 8/12 patients with FTLD and 7/8 controls had negative scans. Of the four PIB-positive patients with FTLD, two had (18)F-FDG scans that suggested AD, and two had (18)F-FDG scans suggestive of FTLD. Mean DVRs were higher in AD than in FTLD in whole brain, lateral frontal, precuneus, and lateral temporal cortex (p < 0.05), while DVRs in FTLD did not significantly differ from controls.PET imaging with (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) helps discriminate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). Pathologic correlation is needed to determine whether patients with PIB-positive FTLD represent false positives, comorbid FTLD/AD pathology, or AD pathology mimicking an FTLD clinical syndrome.

View details for Web of Science ID 000245570100008

View details for PubMedID 17420404

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Sundari Chetty

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