Human ESC-derived Neural Rosettes and Neural Stem Cell Progression

Developmental Biology Program, Division of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cold Spring Harbor Symposia on Quantitative Biology 03/2009; 73:377-87. DOI: 10.1101/sqb.2008.73.052
Source: PubMed

ABSTRACT Neural stem cells (NSCs) are defined by their ability to self-renew while retaining differentiation potential toward the three main central nervous system (CNS) lineages: neurons, astrocytes, and oligodendrocytes. A less appreciated fact about isolated NSCs is their narrow repertoire for generating specific neuron types, which are generally limited to a few region-specific subtypes such as GABAergic and glutamatergic neurons. Recent studies in human embryonic stem cells have identified a novel neural stem cell stage at which cells exhibit plasticity toward generating a broad range of neuron types in response to appropriate developmental signals. Such rosette-stage NSCs (R-NSCs) are also distinct from other NSC populations by their specific cytoarchitecture, gene expression, and extrinsic growth requirements. Here, we discuss the properties of R-NSCs within the context of NSC biology and define some of the key questions for future investigation. R-NSCs may represent the first example of a NSC population capable of recreating the full cellular diversity of the developing CNS, with implications for both basic stem cell biology and translational applications in regenerative medicine and drug discovery.

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Available from: Yechiel Elkabetz, Mar 01, 2014
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    • "ES cells (and iPSCs) are also excellent in vitro model systems with which to approach basic mechanistic studies of developmental processes, especially early steps in human development, and such studies are revealing similar roles for Notch activity in regulation of cell-fate decisions and found in endogenous NSCs in vivo. For example, Notch signaling has similar roles in directing early cellfate decisions, promoting proliferation, and maintaining progenitors and can be selectively inactivated to direct/ enhance neural differentiation of specific types of neurons (Guentchev and McKay, 2006; Elkabetz and Studer, 2008; Fox et al., 2008; Yu et al., 2008; Kobayashi and Kageyama, 2010; Kobayashi et al., 2009; Das et al., 2010; Borghese et al., 2010; Reh et al., 2010). Thus, directing ES/iPSCs into specific types of cells through Notch signaling has great promise for clinical applications, especially given the ability to direct and control their neuronal differentiation through pharmacological regimens. "
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    ABSTRACT: The history of Notch signaling goes back almost a century, to some of the earliest studies of Drosophila development. Since this time, Notch signaling has been found to underlie many evolutionary conserved developmental processes in multiple systems and across phyla. In particular, Notch signaling plays a key role in both invertebrate and vertebrate nervous system development. From the initial identification of its neurogenic phenotype in flies, through recently reported roles in adult mammalian neurogenesis, Notch is best known for mediating lateral inhibition, a process that simultaneously regulates neural differentiation and maintenance of progenitor pools. Here, the authors review these classic functions of Notch, focusing on contributions from higher order vertebrate neurogenic model systems that reveal conserved molecular regulatory pathways similar to those operating in Drosophila. In addition, the authors review Notch's roles in gliogenesis, embryonic stem cells, and exciting new roles in diversifying neuronal subtypes, regulating neuronal morphology, synaptic plasticity, and neuronal activity, revealing that Notch is not(ch) your ordinary signaling pathway.
    Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS, volume 1 edited by John LR Rubenstein, Pasko Rakic, 01/2013: chapter 17: pages 313-332; Academic Press, Oxford., ISBN: 9780123972651
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    • "hESC culture and neural induction. Differentiation of hESCs into neurons was performed using a modification of previously described methods (Elkabetz and Studer, 2008; Li et al., 2008; Cho et al., 2011). "
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    ABSTRACT: After transplantation, individual stem cell-derived neurons can functionally integrate into the host CNS; however, evidence that neurons derived from transplanted human embryonic stem cells (hESCs) can drive endogenous neuronal network activity in CNS tissue is still lacking. Here, using multielectrode array recordings, we report activation of high-frequency oscillations in the β and γ ranges (10-100 Hz) in the host hippocampal network via targeted optogenetic stimulation of transplanted hESC-derived neurons.
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    • "Subsequently R-NSCs were mechanically passaged onto culture dishes precoated with 15 mg/mL polyornithine and 1 mg/mL laminin (Po/Lam) in N2 medium supplemented with SHH (200 ng/mL), FGF8 (100 ng/mL), ascorbic acid (200 mg/mL), and BDNF (20 ng/mL) and harvested after 1 wk in culture. NPCs were derived from R-NSCs upon extended culture in FGF2/EGF (day 95 of differentiation) as described previously (Elkabetz et al. 2008). MPCs were generated as in Barberi et al. (2007). "
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    ABSTRACT: MicroRNAs are important regulators in many cellular processes, including stem cell self-renewal. Recent studies demonstrated their function as pluripotency factors with the capacity for somatic cell reprogramming. However, their role in human embryonic stem (ES) cells (hESCs) remains poorly understood, partially due to the lack of genome-wide strategies to identify their targets. Here, we performed comprehensive microRNA profiling in hESCs and in purified neural and mesenchymal derivatives. Using a combination of AGO cross-linking and microRNA perturbation experiments, together with computational prediction, we identified the targets of the miR-302/367 cluster, the most abundant microRNAs in hESCs. Functional studies identified novel roles of miR-302/367 in maintaining pluripotency and regulating hESC differentiation. We show that in addition to its role in TGF-β signaling, miR-302/367 promotes bone morphogenetic protein (BMP) signaling by targeting BMP inhibitors TOB2, DAZAP2, and SLAIN1. This study broadens our understanding of microRNA function in hESCs and is a valuable resource for future studies in this area.
    Genes & development 10/2011; 25(20):2173-86. DOI:10.1101/gad.17221311 · 12.64 Impact Factor