High-content phenotypic screening and triaging strategy to identify small molecules driving oligodendrocyte progenitor cell differentiation.
J Biomol Screen
; 20(3): 382-90, 2015 Mar.
Article
en En
| MEDLINE
| ID: mdl-25394729
ABSTRACT
Multiple Sclerosis is a demyelinating disease of the CNS and the primary cause of neurological disability in young adults. Loss of myelinating oligodendrocytes leads to neuronal dysfunction and death and is an important contributing factor to this disease. Endogenous oligodendrocyte precursor cells (OPCs), which on differentiation are responsible for replacing myelin, are present in the adult CNS. As such, therapeutic agents that can stimulate OPCs to differentiate and remyelinate demyelinated axons under pathologic conditions may improve neuronal function and clinical outcome. We describe the details of an automated, cell-based, morphometric-based, high-content screen that is used to identify small molecules eliciting the differentiation of OPCs after 3 days. Primary screening was performed using rat CG-4 cells maintained in culture conditions that normally support a progenitor cell-like state. From a library of 73,000 diverse small molecules within the Sanofi collection, 342 compounds were identified that increased OPC morphological complexity as an indicator of oligodendrocyte maturation. Subsequent to the primary high-content screen, a suite of cellular assays was established that identified 22 nontoxic compounds that selectively stimulated primary rat OPCs but not C2C12 muscle cell differentiation. This rigorous triaging yielded several chemical series for further expansion and bio- or cheminformatics studies, and their compelling biological activity merits further investigation.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fenotipo
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Diferenciación Celular
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Oligodendroglía
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Evaluación Preclínica de Medicamentos
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Bibliotecas de Moléculas Pequeñas
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Ensayos Analíticos de Alto Rendimiento
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Células-Madre Neurales
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
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Screening_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article