Human stem cells for modeling neurological disorders: Accelerating the drug discovery pipeline

Crook, Jeremy Micah; Kobayashi, Nao

doi:10.1002/jcb.21967

Cited by 21 publications

(15 citation statements)

References 57 publications

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“…Embryonic stem cells (ESCs) are derived from the inner cell mass of growing blastocysts and have been widely used in developmental biology, drug discovery and cell therapies (Crook and Kobayashi, 2008;Kirouac and Zandstra, 2008). Neural induction from ESCs is regulated by many transcription factors and signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling

et al. 2015

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Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination.

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Section: Introductionmentioning

confidence: 99%

Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling

et al. 2015

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“…Crook and Kobayashi proposed that the traditional inefficiencies, high attrition rates, protracted R&D cycles, and elevated costs inherent to drug development can be curtailed by using relatively inexpensive and high-throughput in vitro human stem cell-based assays as a first phase of discovery and preclinical development in the pharmaceutical pipeline (Crook and Kobayashi, 2008). iPS cells can be used to improve the efficiency of novel drug discovery by providing disease-and patient-specific cells with particular gene expression profile.…”

Section: Establishment Of Disease Modelsmentioning

confidence: 99%

“…This is because sporadic diseases may be caused by epigenetic changes to cells that are subsequently removed through reprogramming (Ebert and Svendsen, 2010). While the method of reprogramming is likely to be less of an issue for disease modeling and drug discovery, it remains to be shown that viral integration and transduction of foreign genes does not confound endogenous cellular processes (Crook and Kobayashi, 2008).…”

Section: Establishment Of Disease Modelsmentioning

confidence: 99%

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The applications of induced pluripotent stem (iPS) cells in drug development

Yang¹,

Wang

Liu³

et al. 2011

Front. Biol.

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The introduction of induced pluripotent stem (iPS) cells has been a milestone in the field of regenerative medicine and drug discovery. iPS cells can provide a continuous and individualized source of stem cells and are considered to hold great potential for economically feasible personalized stem cell therapy. Various diseases might potentially be cured by iPS cell-based therapy including Parkinson's disease, Alzheimer's disease, Huntington disease, ischemic heart disease, diabetes and so on. Moreover, iPS cells derived from patients suffering from unique incurable diseases can be developed into patient-and disease-specific cell lines. These cells can be used as an effective approach to study the mechanisms of diseases, providing useful tools for drug discovery, development and evaluation. The development of suitable methods for the culture and expansion of iPS cells and their differentiated progenies make feasible modern drug discovery techniques such as high-throughput screening. Furthermore, iPS cells can be applied in the field of toxicological and pharmacokinetics tests. This review focuses on the applications of iPS cells in the field of pharmaceutical industry.

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“…Toxicologists have employed Embryonic Stem Cells (ESCs) to investigate the genotoxic effects of environmental pollutants (Chan 2008;Vinoth et al 2008). In the pharmaceutical industry, stem cell-based assays been established as a low cost, high throughput approach to assess efficacy and toxicity in the early stages of drug development (Crook and Kobayashi 2008). Most importantly, stem cells have been exploited as in vitro models of differentiation.…”

Section: Introductionmentioning

confidence: 99%

Efficient method for generating nuclear fractions from marrow stromal cells

Woodbury¹,

Len

Reynolds³

et al. 2008

Cytotechnology

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Stem cells have received significant attention for their envisioned potential to treat currently unapproachable diseases. No less important is the utility of stem cells to serve as model systems of differentiation. Analyses at the transcriptome, miRNA and proteome levels have yielded valuable insights into events underlying stem cell differentiation. Proteomic analysis is often cumbersome, detecting changes in hundreds of proteins that require subsequent identification and validation. Targeted analysis of nuclear constituents would simplify proteomic studies, focusing efforts on transcription factor abundance and modification. To facilitate such studies, a simple and efficient methodology to isolate pure nuclear fractions from Marrow Stromal Cells (MSCs), a clinically relevant stem cell population, has been developed. The modified protocol greatly enhances cell disruption, yielding free nuclei without attached cell body remnants. Light and electron microscopic analysis of purified nuclei demonstrated that preparations contained predominantly intact nuclei with minimal cytoplasmic contamination. Western analysis revealed an approximately eightfold enrichment of the transcription factor CREB in the isolated nuclei over that in the starting homogenates. This simple method for isolation of highly purified nuclear fractions from stem cell populations will allow rigorous examination of nuclear proteins critical for differentiation.

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Human stem cells for modeling neurological disorders: Accelerating the drug discovery pipeline

Cited by 21 publications

References 57 publications

Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling

Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling

The applications of induced pluripotent stem (iPS) cells in drug development

Efficient method for generating nuclear fractions from marrow stromal cells

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