Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage.
Neural stem cells (NSCs) yield both neuronal and glial progeny, but their differentiation potential toward multiple region-specific neuron types remains remarkably poor. In contrast, embryonic stem cell (ESC) progeny readily yield region-specific neuronal fates in response to appropriate developmental signals. Here we demonstrate prospective and clonal isolation of neural rosette cells (termed R-NSCs), a novel NSC type with broad differentiation potential toward CNS and PNS fates and capable of in vivo engraftment. R-NSCs can be derived from human and mouse ESCs or from neural plate stage embryos. While R-NSCs express markers classically associated with NSC fate, we identified a set of genes that specifically mark the R-NSC state. Maintenance of R-NSCs is promoted by activation of SHH and Notch pathways. In the absence of these signals, R-NSCs rapidly lose rosette organization and progress to a more restricted NSC stage. We propose that R-NSCs represent the first characterized NSC stage capable of responding to patterning cues that direct differentiation toward region-specific neuronal fates. In addition, the R-NSC-specific genetic markers presented here offer new tools for harnessing the differentiation potential of human ESCs.
Elkabetz
Yechiel
Y
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Panagiotakos
Georgia
G
Al Shamy
George
G
Socci
Nicholas D
ND
Tabar
Viviane
V
Studer
Lorenz
L
D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D051379:Mice; D054258:Neural Plate / Q000166:cytology; D046569:Neuroepithelial Cells / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction
D053823:Hedgehog Proteins; D051880:Receptors, Notch; C509239:SHH protein, human