Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells.
Human neural progenitor cells provide a source for cell replacement therapy to treat neurodegenerative diseases. Therefore, there is great interest in mechanisms and tools to direct the fate of multipotent progenitor cells during their differentiation to increase the yield of a desired cell type. We tested small molecule inhibitors of glycogen synthase kinase-3 (GSK-3) for their functionality and their influence on neurogenesis using the human neural progenitor cell line ReNcell VM. Here we report the enhancement of neurogenesis of human neural progenitor cells by treatment with GSK-3 inhibitors. We tested different small molecule inhibitors of GSK-3 i.e. LiCl, sodium-valproate, kenpaullone, indirubin-3-monoxime and SB-216763 for their ability to inhibit GSK-3 in human neural progenitor cells. The highest in situ GSK-3 inhibitory effect of the drugs was found for kenpaullone and SB-216763. Accordingly, kenpaullone and SB-216763 were the only drugs tested in this study to stimulate the Wnt/β-catenin pathway that is antagonized by GSK-3. Analysis of human neural progenitor differentiation revealed an augmentation of neurogenesis by SB-216763 and kenpaullone, without changing cell cycle exit or cell survival. Small molecule inhibitors of GSK-3 enhance neurogenesis of human neural progenitor cells and may be used to direct the differentiation of neural stem and progenitor cells in therapeutic applications.
Neurobiological Laboratory, Department of Neurology, University of Rostock, Germany.
Christian
C
Lange
Eilhard
E
Mix
Jana
J
Frahm
Anne
A
Glass
Jana
J
Müller
Oliver
O
Schmitt
Anne-Caroline
AC
Schmöle
Kristin
K
Klemm
Stefanie
S
Ortinau
Rayk
R
Hübner
Moritz J
MJ
Frech
Andreas
A
Wree
Arndt
A
Rolfs
D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D018709:Statistics, Nonparametric; D013997:Time Factors
D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3