TY  - JOUR
AU  - Reinhardt, Peter
AU  - Glatza, Michael
AU  - Hemmer, Kathrin
AU  - Tsytsyura, Yaroslav
AU  - Thiel, Cora S
AU  - Höing, Susanne
AU  - Moritz, Sören
AU  - Parga, Juan A
AU  - Wagner, Lydia
AU  - Bruder, Jan M
AU  - Wu, Guangming
AU  - Schmid, Benjamin
AU  - Röpke, Albrecht
AU  - Klingauf, Jürgen
AU  - Schwamborn, Jens C
AU  - Gasser, Thomas
AU  - Schöler, Hans R
AU  - Sterneckert, Jared
TI  - Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling.
JO  - PLOS ONE
VL  - 8
IS  - 3
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-03171
SP  - e59252
PY  - 2013
AB  - 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.
KW  - Cell Differentiation: genetics
KW  - Cell Differentiation: physiology
KW  - Cells, Cultured
KW  - Electrophysiology
KW  - Epithelial Cells: cytology
KW  - Epithelial Cells: metabolism
KW  - Humans
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
KW  - Motor Neurons: cytology
KW  - Motor Neurons: metabolism
KW  - Neural Crest: cytology
KW  - Neural Crest: metabolism
KW  - Neural Stem Cells: cytology
KW  - Neural Stem Cells: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - Neurodegenerative Diseases: metabolism
KW  - Neurons: cytology
KW  - Neurons: metabolism
KW  - Protein-Serine-Threonine Kinases: genetics
KW  - Protein-Serine-Threonine Kinases: metabolism
KW  - LRRK2 protein, human (NLM Chemicals)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23533608
C2  - pmc:PMC3606479
DO  - DOI:10.1371/journal.pone.0059252
UR  - https://pub.dzne.de/record/136849
ER  -