Journal Article

DZNE-2020-03171

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling.

Reinhardt, P. ; Glatza, M. ; Hemmer, K. ; Tsytsyura, Y. ; Thiel, C. S. ; Höing, S. ; Moritz, S. ; Parga, J. A. ; Wagner, L. ; Bruder, J. M. ; Wu, G. ; Schmid, B.DZNE* ; Röpke, A. ; Klingauf, J. ; Schwamborn, J. C. ; Gasser, T.DZNE* ; Schöler, H. R. (Corresponding author) ; Sterneckert, J.

2013
PLOS San Francisco, California, US

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Please use a persistent id in citations: doi:10.1371/journal.pone.0059252

Abstract: Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even small variability within the cell populations for screening could easily invalidate an entire campaign. Neurodegenerative assays are particularly challenging because neurons are post-mitotic and cannot be expanded for implementation in HTS. Therefore, HTS for neuroprotective compounds requires a cell type that is robustly expandable and able to differentiate into all of the neuronal subtypes involved in disease pathogenesis. Here, we report the derivation and propagation using only small molecules of human neural progenitor cells (small molecule neural precursor cells; smNPCs). smNPCs are robust, exhibit immortal expansion, and do not require cumbersome manual culture and selection steps. We demonstrate that smNPCs have the potential to clonally and efficiently differentiate into neural tube lineages, including motor neurons (MNs) and midbrain dopaminergic neurons (mDANs) as well as neural crest lineages, including peripheral neurons and mesenchymal cells. These properties are so far only matched by pluripotent stem cells. Finally, to demonstrate the usefulness of smNPCs we show that mDANs differentiated from smNPCs with LRRK2 G2019S are more susceptible to apoptosis in the presence of oxidative stress compared to wild-type. Therefore, smNPCs are a powerful biological tool with properties that are optimal for large-scale disease modeling, phenotypic screening, and studies of early human development.

Keyword(s): Cell Differentiation: genetics (MeSH) ; Cell Differentiation: physiology (MeSH) ; Cells, Cultured (MeSH) ; Electrophysiology (MeSH) ; Epithelial Cells: cytology (MeSH) ; Epithelial Cells: metabolism (MeSH) ; Humans (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (MeSH) ; Motor Neurons: cytology (MeSH) ; Motor Neurons: metabolism (MeSH) ; Neural Crest: cytology (MeSH) ; Neural Crest: metabolism (MeSH) ; Neural Stem Cells: cytology (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; Neurodegenerative Diseases: genetics (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Neurons: cytology (MeSH) ; Neurons: metabolism (MeSH) ; Protein-Serine-Threonine Kinases: genetics (MeSH) ; Protein-Serine-Threonine Kinases: metabolism (MeSH) ; LRRK2 protein, human ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Protein-Serine-Threonine Kinases

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Contributing Institute(s):

1. Zebrafish Models (Zebrafish Models ; AG Schmid ; AG Schmid München)
2. Parkinson Genetics (AG Gasser 1)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2013

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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