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000136849 0247_ $$2doi$$a10.1371/journal.pone.0059252
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000136849 037__ $$aDZNE-2020-03171
000136849 041__ $$aEnglish
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000136849 1001_ $$0P:(DE-HGF)0$$aReinhardt, Peter$$b0
000136849 245__ $$aDerivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling.
000136849 260__ $$aSan Francisco, California, US$$bPLOS$$c2013
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000136849 520__ $$aPhenotypic 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.
000136849 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000136849 536__ $$0G:(DE-HGF)POF3-345$$a345 - Population Studies and Genetics (POF3-345)$$cPOF3-345$$fPOF III$$x1
000136849 542__ $$2Crossref$$i2013-03-22$$uhttp://creativecommons.org/licenses/by/4.0/
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000136849 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLRRK2 protein, human
000136849 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000136849 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProtein-Serine-Threonine Kinases
000136849 650_2 $$2MeSH$$aCell Differentiation: genetics
000136849 650_2 $$2MeSH$$aCell Differentiation: physiology
000136849 650_2 $$2MeSH$$aCells, Cultured
000136849 650_2 $$2MeSH$$aElectrophysiology
000136849 650_2 $$2MeSH$$aEpithelial Cells: cytology
000136849 650_2 $$2MeSH$$aEpithelial Cells: metabolism
000136849 650_2 $$2MeSH$$aHumans
000136849 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000136849 650_2 $$2MeSH$$aMotor Neurons: cytology
000136849 650_2 $$2MeSH$$aMotor Neurons: metabolism
000136849 650_2 $$2MeSH$$aNeural Crest: cytology
000136849 650_2 $$2MeSH$$aNeural Crest: metabolism
000136849 650_2 $$2MeSH$$aNeural Stem Cells: cytology
000136849 650_2 $$2MeSH$$aNeural Stem Cells: metabolism
000136849 650_2 $$2MeSH$$aNeurodegenerative Diseases: genetics
000136849 650_2 $$2MeSH$$aNeurodegenerative Diseases: metabolism
000136849 650_2 $$2MeSH$$aNeurons: cytology
000136849 650_2 $$2MeSH$$aNeurons: metabolism
000136849 650_2 $$2MeSH$$aProtein-Serine-Threonine Kinases: genetics
000136849 650_2 $$2MeSH$$aProtein-Serine-Threonine Kinases: metabolism
000136849 7001_ $$0P:(DE-HGF)0$$aGlatza, Michael$$b1
000136849 7001_ $$0P:(DE-HGF)0$$aHemmer, Kathrin$$b2
000136849 7001_ $$0P:(DE-HGF)0$$aTsytsyura, Yaroslav$$b3
000136849 7001_ $$0P:(DE-HGF)0$$aThiel, Cora S$$b4
000136849 7001_ $$0P:(DE-HGF)0$$aHöing, Susanne$$b5
000136849 7001_ $$0P:(DE-HGF)0$$aMoritz, Sören$$b6
000136849 7001_ $$0P:(DE-HGF)0$$aParga, Juan A$$b7
000136849 7001_ $$0P:(DE-HGF)0$$aWagner, Lydia$$b8
000136849 7001_ $$0P:(DE-HGF)0$$aBruder, Jan M$$b9
000136849 7001_ $$0P:(DE-HGF)0$$aWu, Guangming$$b10
000136849 7001_ $$0P:(DE-2719)9000388$$aSchmid, Benjamin$$b11$$udzne
000136849 7001_ $$0P:(DE-HGF)0$$aRöpke, Albrecht$$b12
000136849 7001_ $$0P:(DE-HGF)0$$aKlingauf, Jürgen$$b13
000136849 7001_ $$0P:(DE-HGF)0$$aSchwamborn, Jens C$$b14
000136849 7001_ $$0P:(DE-2719)2320009$$aGasser, Thomas$$b15$$udzne
000136849 7001_ $$0P:(DE-HGF)0$$aSchöler, Hans R$$b16$$eCorresponding author
000136849 7001_ $$0P:(DE-HGF)0$$aSterneckert, Jared$$b17
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