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Journal of Biomolecular Screening
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Identification of Small-Molecule Modulators of Mouse SVZ Progenitor Cell Proliferation and Differentiation Through High-Throughput Screening

Yaping Liu

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania, yaping_liu{at}merck.com

Raul Lacson

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Jason Cassaday

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

David A. Ross

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Anthony Kreamer

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Edward Hudak

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Richard Peltier

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Donna Mclaren

Department of Neuroscience, Merck & Co., Terlings Park, UK

Ignacio Muñoz-Sanjuan

Department of Neuroscience, Merck & Co., Terlings Park, UK

Francesca Santini

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Berta Strulovici

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Marc Ferrer

Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania

Adult mouse subventricular zone (SVZ) neural stem/progenitor cells are multipotent self-renewing cells that retain the capacity to generate the major cell types of the central nervous system in vitro and in vivo. The relative ease of expanding SVZ cells in culture as neurospheres makes them an ideal model for carrying out large-scale screening to identify compounds that regulate neural progenitor cell proliferation and differentiation. The authors have developed an adenosine triphosphate—based cell proliferation assay using adult SVZ cells to identify small molecules that activate or inhibit progenitor cell proliferation. This assay was miniaturized to a 1536-well format for high-throughput screening (HTS) of >1 million small-molecule compounds, and 325 and 581 compounds were confirmed as potential inducers of SVZ cell proliferation and differentiation, respectively. A number of these compounds were identified as having a selective proliferative and differentiation effect on SVZ cells versus mouse Neuro2a neuroblastoma cells. These compounds can potentially be useful pharmacological tools to modulate resident stem cells and neurogenesis in the adult brain. This study represents a novel application of primary somatic stem cells in the HTS of a large-scale compound library. (Journal of Biomolecular Screening 2009:319-329)

Key Words: subventricular zone (SVZ) • neural progenitor cells • proliferation • differentiation • CellTiter-GloTM • high-throughput screening (HTS)

Journal of Biomolecular Screening, Vol. 14, No. 4, 319-329 (2009)
DOI: 10.1177/1087057109332596
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