A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke

Pollock, Kenneth H.; Stroemer, Paul; Patel, Sara; Stevanato, Lara; Hope, Andrew; Miljan, Erik; Dong, Zhou; Hodges, Helen; Price, John; Sinden, John D.

doi:10.1016/j.expneurol.2005.12.011

Cited by 255 publications

(277 citation statements)

References 42 publications

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“…Such cell lines, recently established from fetal brains using v-myc immortalization, 17,19,30,31 retain self-renewal potential and capacity to differentiate into the three major neural lineages, astrocytes, oligodendrocytes and neurons. Interestingly, transplantation of a conditionally immortal human neural stem cell line into the brain has allowed functional recovery in a rat model of stroke disability.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, transplantation of a conditionally immortal human neural stem cell line into the brain has allowed functional recovery in a rat model of stroke disability. 17 To get an insight into the mechanisms of neuronal degeneration in A-T, we used the human neural stem cell line ihNSC, 19 to evaluate the ATM-dependent response to DNA damage and the differentiation potential following ATM depletion. We have shown that these cells constitutively express at D0 stage ATM, ATR, Nbs1, Mre11, RAD50, Chk1, Chk2 and Smc1, but the levels of these proteins change upon differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…13 Genetically stable human neural stem cell lines (ihNSCs), which maintain self-renewal capacity and differentiation potential in vitro, can provide an important tool for neurobiological investigations. [17][18][19] In this study, we showed that in ihNSCs, the regulation of the ATM-dependent pathway in response to ionizing radiation (IR) induced DNA damage and the outcome of ATM protein ablation by short hairpin RNA (shRNA) interference on survival, self-renewal and terminal differentiation. We show that the ablation of ATM in ihNSCs does not affect the proliferative activity, suppresses the response to DNA damage, attenuates the apoptosis associated with differentiation and mildly affects the differentiation and survival of GalC þ oligodendrocytes.…”

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DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

et al. 2009

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Ataxia-telangiectasia (A-T) is a neurodegenerative disorder caused by defects in the ATM kinase, a component of the DNA-damage response (DDR). Here, we employed an immortalized human neural stem-cell line (ihNSC) capable of differentiating in vitro into neurons, oligodendrocytes and astrocytes to assess the ATM-dependent response and outcome of ATM ablation. The time-dependent differentiation of ihNSC was accompanied by an upregulation of ATM and DNA-PK, sharp downregulation of ATR and Chk1, transient induction of p53 and by the onset of apoptosis in a fraction of cells. The response to ionizing radiation (IR)-induced DNA lesions was normal, as attested by the phosphorylation of ATM and some of its substrates (e.g., Nbs1, Smc1, Chk2 and p53), and by the kinetics of c-H2AX nuclear foci formation. Depletion in these cells of ATM by shRNA interference (shATM) attenuated the differentiation-associated apoptosis and response to IR, but left unaffected the growth, self-renewal and genomic stability. shATM cells generated a normal number of MAP2/b-tubulin III þ neurons, but a reduced number of GalC þ oligodendrocytes, which were nevertheless more susceptible to oxidative stress. Altogether, these findings highlight the potential of ihNSCs as an in vitro model system to thoroughly assess, besides ATM, the role of DDR genes in neurogenesis and/or neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

et al. 2009

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“…Several human NSC lines have been produced from whole human fetal brain or telecephalic region using the DNA sequence of the v-myc gene isolated from the avian myelocytic leukemia virus [13; 14; 19]. Recently, a new stem cell line was generated from human fetal cortical tissue by a conditional immortalizing approach [20]. The immortalizing transgene encodes a fusion protein comprising a growth promoting gene, c-myc, and a tamoxifen-regulated hormone receptor.…”

Section: Introductionmentioning

confidence: 99%

Generation of human cortical neurons from a new immortal fetal neural stem cell line

Cacci

Villa

Parmar

et al. 2007

Experimental Cell Research

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Isolation and expansion of neural stem cells (NSCs) of human origin are crucial for successful development of cell therapy approaches in neurodegenerative diseases. Different epigenetic and genetic immortalization strategies have been established for long-term maintenance and expansion of these cells in vitro. Here we report the generation of a new, clonal NSC (hc-NSC) line, derived from human fetal cortical tissue, based on v-myc immortalization. Using immunocytochemistry, we show that these cells retain the characteristics of NSCs after more than 50 passages. Under proliferation conditions, when supplemented with epidermal and basic fibroblast growth factors, the hc-NSCs expressed neural stem/progenitor cell markers like nestin, vimentin and Sox2. When growth factors were withdrawn, proliferation and expression of v-myc and telomerase were dramatically reduced, and the hc-NSCs differentiated into glia. and neurons (mostly glutamatergic and GABAergic, as well as tyrosine hydroxylase-positive, presumably dopaminergic neurons). RT-PCR analysis showed that the hc-NSCs retained expression of Pax6, Emx2 and Neurogenin2, which are genes associated with regionalization and cell commitment in cortical precursors during brain development. Our data indicate that this hc-NSC line could be useful for exploring the potential of human NSCs to replace dead or damaged cortical cells in animal models of acute and chronic neurodegenerative diseases. Taking advantage of its clonality and homogeneity, this cell line will also be a valuable experimental tool to study the regulatory role of intrinsic and extrinsic factors in human NSC biology. (c) 2006 Elsevier Inc. All rights reserved

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“…3,4 Subsequent in vivo studies supported the safety and efficacy of CTX-DP and SB623 following their transplantation into animal models of stroke. 6,7 Moreover, insights into these cells' mechanisms of action have postulated graft-induced endogenous repair processes.…”

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Preliminary Reports of Stereotaxic Stem Cell Transplants in Chronic Stroke Patients

Borlongan

2016

Molecular Therapy

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A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke

Cited by 255 publications

References 42 publications

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

Generation of human cortical neurons from a new immortal fetal neural stem cell line

Preliminary Reports of Stereotaxic Stem Cell Transplants in Chronic Stroke Patients

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