High-Throughput Screening Assay for the Identification of Compounds Regulating Self-Renewal and Differentiation in Human Embryonic Stem Cells

Sabrina C. Desbordes; Dimitris G. Placantonakis; Anthony Ciro; Nicholas D. Socci; Gabsang Lee; Hakim Djaballah; Lorenz Studer

doi:10.1016/j.stem.2008.05.010

High-Throughput Screening Assay for the Identification of Compounds Regulating Self-Renewal and Differentiation in Human Embryonic Stem Cells

Sabrina C. Desbordes, Dimitris G. Placantonakis, Anthony Ciro, Nicholas D. Socci, Gabsang Lee, Hakim Djaballah, Lorenz Studer

Research output: Contribution to journal › Article › peer-review

188 Scopus citations

Abstract

High-throughput screening (HTS) of chemical libraries has become a critical tool in basic biology and drug discovery. However, its implementation and the adaptation of high-content assays to human embryonic stem cells (hESCs) have been hampered by multiple technical challenges. Here we present a strategy to adapt hESCs to HTS conditions, resulting in an assay suitable for the discovery of small molecules that drive hESC self-renewal or differentiation. Use of this new assay has led to the identification of several marketed drugs and natural compounds promoting short-term hESC maintenance and compounds directing early lineage choice during differentiation. Global gene expression analysis upon drug treatment defines known and novel pathways correlated to hESC self-renewal and differentiation. Our results demonstrate feasibility of hESC-based HTS and enhance the repertoire of chemical compounds for manipulating hESC fate. The availability of high-content assays should accelerate progress in basic and translational hESC biology.

Original language	English (US)
Pages (from-to)	602-612
Number of pages	11
Journal	Cell stem cell
Volume	2
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2008.05.010
State	Published - Jun 5 2008
Externally published	Yes

Keywords

STEMCELL

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2008.05.010

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title = "High-Throughput Screening Assay for the Identification of Compounds Regulating Self-Renewal and Differentiation in Human Embryonic Stem Cells",

abstract = "High-throughput screening (HTS) of chemical libraries has become a critical tool in basic biology and drug discovery. However, its implementation and the adaptation of high-content assays to human embryonic stem cells (hESCs) have been hampered by multiple technical challenges. Here we present a strategy to adapt hESCs to HTS conditions, resulting in an assay suitable for the discovery of small molecules that drive hESC self-renewal or differentiation. Use of this new assay has led to the identification of several marketed drugs and natural compounds promoting short-term hESC maintenance and compounds directing early lineage choice during differentiation. Global gene expression analysis upon drug treatment defines known and novel pathways correlated to hESC self-renewal and differentiation. Our results demonstrate feasibility of hESC-based HTS and enhance the repertoire of chemical compounds for manipulating hESC fate. The availability of high-content assays should accelerate progress in basic and translational hESC biology.",

keywords = "STEMCELL",

author = "Desbordes, {Sabrina C.} and Placantonakis, {Dimitris G.} and Anthony Ciro and Socci, {Nicholas D.} and Gabsang Lee and Hakim Djaballah and Lorenz Studer",

note = "Funding Information: We thank the members of the Memorial Sloan-Kettering Cancer Center High-Throughput Screening (MSKCC HTS) Core Facility for their help during the course of this study, especially C. Radu, D. Shum, and G.E. Sanchez. We also thank V. Tabar, Y. Elkabetz, M. Tomishima, F. Lafaille, and H. L{\'o}pez-Schier for critical comments on the manuscript and S. Gong and N. Heintz for providing the Oct4::eGFP BAC. Supported by National Institute of Neurological Disorders and Stroke (NINDS) grant (R21NS44231), The Starr Foundation, Mr. W.H. Goodwin and Mrs. A. Goodwin and the Commonwealth Foundation for Cancer Research, The William Randolph Hearst Foundation, and The Experimental Therapeutics Center of MSKCC. ",

year = "2008",

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language = "English (US)",

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AU - Desbordes, Sabrina C.

AU - Placantonakis, Dimitris G.

AU - Ciro, Anthony

AU - Socci, Nicholas D.

AU - Lee, Gabsang

AU - Djaballah, Hakim

AU - Studer, Lorenz

N1 - Funding Information: We thank the members of the Memorial Sloan-Kettering Cancer Center High-Throughput Screening (MSKCC HTS) Core Facility for their help during the course of this study, especially C. Radu, D. Shum, and G.E. Sanchez. We also thank V. Tabar, Y. Elkabetz, M. Tomishima, F. Lafaille, and H. López-Schier for critical comments on the manuscript and S. Gong and N. Heintz for providing the Oct4::eGFP BAC. Supported by National Institute of Neurological Disorders and Stroke (NINDS) grant (R21NS44231), The Starr Foundation, Mr. W.H. Goodwin and Mrs. A. Goodwin and the Commonwealth Foundation for Cancer Research, The William Randolph Hearst Foundation, and The Experimental Therapeutics Center of MSKCC.

PY - 2008/6/5

Y1 - 2008/6/5

N2 - High-throughput screening (HTS) of chemical libraries has become a critical tool in basic biology and drug discovery. However, its implementation and the adaptation of high-content assays to human embryonic stem cells (hESCs) have been hampered by multiple technical challenges. Here we present a strategy to adapt hESCs to HTS conditions, resulting in an assay suitable for the discovery of small molecules that drive hESC self-renewal or differentiation. Use of this new assay has led to the identification of several marketed drugs and natural compounds promoting short-term hESC maintenance and compounds directing early lineage choice during differentiation. Global gene expression analysis upon drug treatment defines known and novel pathways correlated to hESC self-renewal and differentiation. Our results demonstrate feasibility of hESC-based HTS and enhance the repertoire of chemical compounds for manipulating hESC fate. The availability of high-content assays should accelerate progress in basic and translational hESC biology.

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High-Throughput Screening Assay for the Identification of Compounds Regulating Self-Renewal and Differentiation in Human Embryonic Stem Cells

Abstract

Keywords

ASJC Scopus subject areas

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