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


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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    • "We also employed iPS-derived neural rosettes [22] to evaluate the impact of HCMV on neural differentiation. Cells displaying CPE also showed strong imunoreactivity for ß-tubulin III (Tuj1), suggesting that the infected cells are committed to a neural fate, but neuronal differentiation is inhibited. "
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    ABSTRACT: Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (i) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate.
    PLoS ONE 11/2012; 7(11):e49700. DOI:10.1371/journal.pone.0049700 · 3.23 Impact Factor
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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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2012; 32(45):15837-42. DOI:10.1523/JNEUROSCI.3735-12.2012 · 6.34 Impact Factor
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