Neural precursor cell susceptibility to human cytomegalovirus diverges along glial or neuronal differentiation pathways

Cheeran, Maxim C.-J.; Hu, Shuxian; Ni, Hsiao Tzu; Sheng, Wen S.; Palmquist, Joseph M.; Peterson, Phillip K.; Lokensgard, James R.

doi:10.1002/jnr.20682

Cited by 66 publications

(101 citation statements)

References 39 publications

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“…Cell death induced by HCMV could be the result of a necrotic or an apoptotic process since this assay does not indicate the involved mechanism (Cheeran et al 2005;Odeberg et al 2006). In addition, proliferation assays showed a strong reduction in SK-N-MC proliferation at 7 dpi with both HCMV concentrations.…”

Section: Discussionmentioning

confidence: 96%

“…Interestingly, as the mouse embryonic stem cells are refractory to the infection, differentiated neurons also have shown an apparent refractivity (Cheeran et al 2009). This effect has been suggested to be explained by the expression of the transcription factor C/EBP β and its dominant negative isoform which binds to the enhancer region and inhibits transcription from the HCMV MIEP (Cheeran et al 2005). By this reason, we assessed the role of differentiation in hNS-1 cells at an early stage when some progenitors begin to differentiate and not when the differentiated neurons can be found.…”

Section: Discussionmentioning

confidence: 99%

“…Because our main objective was to describe the earliest effects of HCMV infection, we have used significantly lower MOI than those employed in other reports (Cheeran et al 2005;Odeberg et al 2006Odeberg et al , 2007Luo et al 2008Luo et al , 2010. Instead of showing the deepest impact of the infection, we decided to monitor the progression in different time points, in order to follow slight effects.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, some brain localizations like ventricular and subventricular zones are particularly important; therefore, it is possible that NPCs play a substantial role during neurological damage. Previous studies have shown that CMV infection in NPC results in differentiation inhibition, reduced proliferation, cellular signaling interference, and cell death; together, these effects may produce migration defects during brain development (Kawasaki and Tsutsui 2003;Cheeran et al 2005;Odeberg et al 2006;Ho and van den Pol 2007). We developed an in vitro model using two different NPCs promoting the use of these cell lines instead of primary cultures.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse models, it has been observed that embryonic stem cells cannot be infected with CMV and they acquire susceptibility through differentiation (Matsukage et al 2006;Kawasaki et al 2011). However, differentiated neurons are also refractory to the infection and this may suggest that only during a precise period during differentiation, the cells can be infected (Cheeran et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

et al. 2015

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Cytomegalovirus (CMV) is the most common cause of congenital infection in developed countries and a major cause of neurological disability in children. Although CMV can affect multiple organs, the most important sequelae of intrauterine infection are related to lesions of the central nervous system. However, little is known about the pathogenesis and the cellular events responsible for neuronal damage in infants with congenital infection. Some studies have demonstrated that neural precursor cells (NPCs) show the greatest susceptibility to CMV infection in the developing brain. We sought to establish an in vitro model of CMV infection of the developing brain in order to analyze the cellular events associated with invasion by this virus. To this end, we employed two cell lines as a permanent source of NPC, avoiding the continuous use of human fetal tissue, the human SK-N-MC neuroblastoma cell line, and an immortalized cell line of human fetal neural origin, hNS-1. We also investigated the effect of the differentiation stage in relation to the susceptibility of these cell lines by comparing the neuroblastoma cell line with the multipotent cell line hNS-1. We found that the effects of the virus were more severe in the neuroblastoma cell line. Additionally, we induced hNS-1 to differentiate and evaluated the effect of CMV in these differentiated cells. Like SK-N-MC cells, hNS-1-differentiated cells were also susceptible to infection. Viability of differentiated hNS-1 cells decreased after CMV infection in contrast to undifferentiated cells. In addition, differentiated hNS-1 cells showed an extensive cytopathic effect whereas the effect was scarce in undifferentiated cells. We describe some of the effects of CMV in neural stem cells, and our observations suggest that the degree of differentiation is important in the acquisition of susceptibility.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

et al. 2015

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Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes

Odeberg

Wolmer

Falci

et al. 2006

J of Neuroscience Research

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Human cytomegalovirus (HCMV) is the most common cause of congenital infections in developed countries, with an incidence varying between 0.5-2.2%. Such infection may be the consequence of either a primary infection or reactivation of a latent infection in the mother and the outcome may vary from asymptomatic to severe brain disorders. Moreover, infants that are asymptomatic at the time of birth may still develop neurologic sequelae at a later age. Our hypothesis is that infection of stem cells of the central nervous system by HCMV alters the proliferation, differentiation or migration of these cells, and thereby gives rise to the brain abnormalities observed. We show that infection of human neural precursor cells (NPCs) with the laboratory strain Towne or the clinical isolate TB40 of HCMV suppresses the differentiation of these cells into astrocytes even at an multiplicity of infection (MOI) as low as 0.1 (by 33% and 67%, respectively). This inhibition required active viral replication and the expression of late HCMV proteins. Infection as late as 24 hr after the onset of differentiation, but not after 72 hr, also prevented the maturation of infected cultures. Furthermore, in cultures infected with TB40 (at an MOI of 1), approximately 54% of the cells were apoptotic and cell proliferation was significantly attenuated. Clearly, HCMV can reduce the capacity of NPCs to differentiate into astrocytes and this effect may provide part of the explanation for the abnormalities in brain development associated with congenital HCMV infection.

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Enhancement of susceptibility of adult mouse brain to cytomegalovirus infection by infusion of epidermal growth factor

Han¹,

Li²,

Kosugi³

et al. 2007

J of Neuroscience Research

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Neural precursor cells, including neural stem and progenitor cells, in the subventricular zone (SVZ) are the main targets for cytomegalovirus (CMV) infection in developing brains. The neural precursor cells in the SVZ of the adult brain have been reported to respond by proliferating after infusion with epidermal growth factor (EGF). Here we report the susceptibility of the precursor cells in the adult mouse brain to murine CMV (MCMV) infection. Adult mouse brains from 10-, 25-, and 70-week-old (W) mice were infused with either phosphate-buffered saline or EGF into the brain for 3 days, and then intracerebrally infected with MCMV for 5 days. The susceptibility of the adult brains to MCMV was significantly increased by infusion of EGF in terms of viral titers and viral antigen-positive cells. The susceptibility of the young adult brain from 10-week-old mice to MCMV was higher than that of the adult brains from 25-week-old or 70-week-old mice. Both the ependymal and the SVZ cells were susceptible to MCMV infection. The number of virus-infected cells in the SVZ was significantly increased by infusion of EGF, whereas the number of infected ependymal cells was not significantly increased. Among the virus-infected cells in the SVZ, 73% were positive for nestin, 87% were positive for Musashi, 86% were positive for GFAP, and 96% were positive for PCNA. These results indicate that the susceptibility of the adult brain to MCMV is correlated with the proliferative ability of the neural precursor cells in the SVZ of the adult brain.

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Neural precursor cell susceptibility to human cytomegalovirus diverges along glial or neuronal differentiation pathways

Cited by 66 publications

References 39 publications

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes

Enhancement of susceptibility of adult mouse brain to cytomegalovirus infection by infusion of epidermal growth factor

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