title: Identification of small-molecule modulators of mouse SVZ progenitor cell proliferation and differentiation through high-throughput screening.
abstract: 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.
authors.affiliation: Department of Automated Biotechnology, Merck & Co., North Wales, Pennsylvania 19454, USA. yaping_liu@merck.com
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.forename: Raul
authors.initials: R
authors.lastname: Lacson
authors.forename: Jason
authors.initials: J
authors.lastname: Cassaday
authors.forename: David A
authors.initials: DA
authors.lastname: Ross
authors.forename: Anthony
authors.initials: A
authors.lastname: Kreamer
authors.forename: Edward
authors.initials: E
authors.lastname: Hudak
authors.forename: Richard
authors.initials: R
authors.lastname: Peltier
authors.forename: Donna
authors.initials: D
authors.lastname: McLaren
authors.forename: Ignacio
authors.initials: I
authors.lastname: Muñoz-Sanjuan
authors.forename: Francesca
authors.initials: F
authors.lastname: Santini
authors.forename: Berta
authors.initials: B
authors.lastname: Strulovici
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000032:analysis*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D054852:Small Molecule Libraries