Neural stem and progenitor cells in health and disease

Ladran, Ian; Tran, N.; Topol, Aaron; Brennand, Kristen J.

doi:10.1002/wsbm.1239

Cited by 27 publications

(18 citation statements)

References 153 publications

(283 reference statements)

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“…The transition from symmetric to asymmetric division is tightly regulated, and precocious asymmetric divisions result in premature differentiation and smaller brains ( Cabernard and Doe, 2009 ; Gauthier-Fisher et al, 2009 ; Egger et al, 2010 ). Aberrant NPC regulation is now linked to many developmental and degenerative disorders of the brain (reviewed by Ladran et al, 2013 ). The stable knockdown of STIM1 significantly reduced NPC proliferation concurrently inducing their spontaneous differentiation to neural progenitors.…”

Section: Discussionmentioning

confidence: 99%

Stable STIM1 Knockdown in Self-Renewing Human Neural Precursors Promotes Premature Neural Differentiation

Gopurappilly

Deb

Chakraborty

et al. 2018

Front. Mol. Neurosci.

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Ca2+ signaling plays a significant role in the development of the vertebrate nervous system where it regulates neurite growth as well as synapse and neurotransmitter specification. Elucidating the role of Ca2+ signaling in mammalian neuronal development has been largely restricted to either small animal models or primary cultures. Here we derived human neural precursor cells (NPCs) from human embryonic stem cells to understand the functional significance of a less understood arm of calcium signaling, Store-operated Ca2+ entry or SOCE, in neuronal development. Human NPCs exhibited robust SOCE, which was significantly attenuated by expression of a stable shRNA-miR targeted toward the SOCE molecule, STIM1. Along with the plasma membrane channel Orai, STIM is an essential component of SOCE in many cell types, where it regulates gene expression. Therefore, we measured global gene expression in human NPCs with and without STIM1 knockdown. Interestingly, pathways down-regulated through STIM1 knockdown were related to cell proliferation and DNA replication processes, whereas post-synaptic signaling was identified as an up-regulated process. To understand the functional significance of these gene expression changes we measured the self-renewal capacity of NPCs with STIM1 knockdown. The STIM1 knockdown NPCs demonstrated significantly reduced neurosphere size and number as well as precocious spontaneous differentiation toward the neuronal lineage, as compared to control cells. These findings demonstrate that STIM1 mediated SOCE in human NPCs regulates gene expression changes, that in vivo are likely to physiologically modulate the self-renewal and differentiation of NPCs.

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Section: Discussionmentioning

confidence: 99%

Stable STIM1 Knockdown in Self-Renewing Human Neural Precursors Promotes Premature Neural Differentiation

Gopurappilly

Deb

Chakraborty

et al. 2018

Front. Mol. Neurosci.

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“…Indeed, neuronal differentiation is an essential process for brain development, especially in children. During the development, neural stem and progenitor cells differentiated into specialized neurons and formed axons and synapses which made neural network and plasticity in brain (Ladran et al 2013). Once neuronal differentiation is interfered by environmental toxic factors in early development, conformational change and disturbed synapse activity of neurons are found and these led to faults of behaviors and cognitive function in human (Heath and Picciotto 2009).…”

Section: Introductionmentioning

confidence: 98%

Taurine resumed neuronal differentiation in arsenite-treated N2a cells through reducing oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction

et al. 2014

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The goal of the study is to investigate the preventive effect of taurine against arsenite-induced arrest of neuronal differentiation in N2a cells. Our results revealed that taurine reinstated the neurite outgrowth in arsenite-treated N2a cells. Meanwhile, arsenite-induced oxidative stress and mitochondrial dysfunction as well as degradation of mitochondria DNA (mtDNA) were also inhibited by co-treatment of taurine. Since oxidative stress and mitochondrial dysfunction is closely associated with endoplasmic reticulum (ER) stress, we further examined indicators of ER stress, 78 kDa glucose-regulated protein (GRP78), and C/EBP-homologous protein (CHOP) protein expression. The results demonstrated that taurine significantly reduced arsenite-induced ER stress in N2a cells. In the parallel experiment, arsenite-induced disruption of intracellular calcium homeostasis was also ameliorated by taurine. The proven bio-function of taurine preserved a preventive effect against deleteriously cross-talking between oxidative stress, mitochondria, and ER. Overall, the results of the study suggested that taurine reinstated neuronal differentiation by inhibiting oxidative stress, ER stress, and mitochondrial dysfunction in arsenite-treated N2a cells.

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“…In the past decade, advances in stem cell biology have led to the emergence of novel powerful tools to investigate complex questions in neurobiology. Human neural stem cells (hNSCs) and the neural progenitor cells (NPCs) that they generate have become a major focus of interest as they provide a renewable and accessible model system in which to investigate basic human neurodevelopment mechanisms and complex neurodevelopmental disorders [ 1 – 4 ]. One major advantage of hNPCs is that they can easily undergo biochemical, pharmacological and genetic manipulations, making them an ideal platform for high-throughput, genetic or small molecule functional screening [ 1 – 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Characterisation of neurons derived from a cortical human neural stem cell line CTX0E16

et al. 2015

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IntroductionConditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native neural cells to investigate physiological mechanisms in both health and disease. However, in order to recognise the utility of such cells, it is critical to determine whether they retain characteristics of their tissue of origin and generate appropriate neural cell types upon differentiation. To this end, we have characterised the conditionally immortalised, cortically-derived, human NPC line, CTX0E16, investigating the molecular and cellular phenotype of differentiated neurons to determine whether they possess characteristics of cortical glutamatergic neurons.MethodsDifferentiated CTX0E16 cells were characterised by assessing expression of several neural fates markers, and examination of developing neuronal morphology. Expression of neurotransmitter receptors, signalling proteins and related proteins were assessed by q- and RT-PCR and complemented by Ca2+ imaging, electrophysiology and assessment of ERK signalling in response to neurotransmitter ligand application. Finally, differentiated neurons were assessed for their ability to form putative synapses and to respond to activity-dependent stimulation.ResultsDifferentiation of CTX0E16 hNPCs predominately resulted in the generation of neurons expressing markers of cortical and glutamatergic (excitatory) fate, and with a typical polarized neuronal morphology. Gene expression analysis confirmed an upregulation in the expression of cortical, glutamatergic and signalling proteins following differentiation. CTX0E16 neurons demonstrated Ca2+ and ERK1/2 responses following exogenous neurotransmitter application, and after 6 weeks displayed spontaneous Ca2+ transients and electrophysiological properties consistent with that of immature neurons. Differentiated CTX0E16 neurons also expressed a range of pre- and post-synaptic proteins that co-localized along distal dendrites, and moreover, displayed structural plasticity in response to modulation of neuronal activity.ConclusionsTaken together, these findings demonstrate that the CTX0E16 hNPC line is a robust source of cortical neurons, which display functional properties consistent with a glutamatergic phenotype. Thus CTX0E16 neurons can be used to study cortical cell function, and furthermore, as these neurons express a range of disease-associated genes, they represent an ideal platform with which to investigate neurodevelopmental mechanisms in native human cells in health and disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0136-8) contains supplementary material, which is available to authorized users.

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Neural stem and progenitor cells in health and disease

Cited by 27 publications

References 153 publications

Stable STIM1 Knockdown in Self-Renewing Human Neural Precursors Promotes Premature Neural Differentiation

Stable STIM1 Knockdown in Self-Renewing Human Neural Precursors Promotes Premature Neural Differentiation

Taurine resumed neuronal differentiation in arsenite-treated N2a cells through reducing oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction

Characterisation of neurons derived from a cortical human neural stem cell line CTX0E16

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