Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Luo, Min; Hannemann, Holger; Kulkarni, Amit; Schwartz, Philip H.; O’Dowd, John M.; Fortunato, Elizabeth A.

doi:10.1128/jvi.02161-09

Cited by 101 publications

(182 citation statements)

References 78 publications

(88 reference statements)

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, when we infected SK-N-MC with the MOI of 0.01, cellular prolongations were observed suggesting cellular differentiation to a neuron-like morphology, an unexpected finding since we did not add any other stimulus that may account for these changes, and this normally does not occur in an spontaneous way (Higgins et al 2009). This induction of differentiation is in agreement with the recent observation of abnormal, spontaneous, and premature differentiation of NPC induced by HCMV (Odeberg et al 2006;Luo et al 2010). The virus concentrations that we used were much lower than those in previous studies, what may explain the delayed effect observed.…”

Section: Discussionsupporting

confidence: 76%

“…Altogether, these observations suggest that cellular differentiation is stimulated in early stages of infection and that cells tend to fuse forming syncytia as viral concentration increases or time after infection progresses. A possible explanation for this latter effect can be a distinct regulation of transcription factors such as SOX2 which is related to embryonic development and stem cell self-renewal and expression of some receptors like EGFR as well as cytoskeleton components (Jafferji et al 2009;Luo et al 2010). Nevertheless, the relevance of HCMV-induced differentiation in the context of CNS development and finding why it is reversed when viral concentration increases are a matter for further investigation.…”

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, cytopathic effect (CPE) in these cells at the multiplicity of infection (MOI) of three plaque formation units (PFU) per cell consisted in formation of syncytia, which can be the result of viral cell to cell dissemination (Luo et al 2008). Infection of these cells may increase the apoptosis frequency and inhibit neuronal and glia differentiation; however, this effect remains controversial since it has also been reported that CMV infection may cause a spontaneous, premature, and abnormal NPC differentiation (Odeberg et al 2006(Odeberg et al , 2007Luo et al 2010).…”

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…38,46,47,53,63 CMV infection causes NSPCs to alter their differentiation program, and it inhibits the proliferation and induces the apoptosis of NSPCs. 47,62,64 Whole-genome expression analysis found rapid downregulation of the mRNA levels of several genes important for maintaining NSPC multipotency and for establishing their neural identity (nestin, doublecortin, sex-determining home box 2 and glial fibrillary acidic protein). 64 It is thus possible that HCMV infection causes in utero CNS defects by inducing both premature and abnormal differentiation of NSPCs.…”

Section: Cmv-induced Developmental Brain Abnormalitiesmentioning

confidence: 99%

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

et al. 2014

View full text Add to dashboard Cite

Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8 1 T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

show abstract

Cerebral cortex development: an outside‐in perspective

2017

View full text Add to dashboard Cite

The cerebral cortex is a complex structure that contains different classes of neurons distributed within six layers and regionally organized into highly specialized areas. Cortical layering arises during embryonic development in an inside-out manner as forebrain progenitors proliferate and generate distinct waves of interneurons and projection neurons. Radial glial cells (RGCs) derive from neuroepithelial cells and are the founding cortical progenitors. At the onset of corticogenesis, RGCs expand their pool by proliferative divisions. As corticogenesis proceeds, they gradually undergo differentiative divisions to either generate neurons directly (direct neurogenesis) or indirectly via production of intermediate progenitors that further divide to generate pairs of neurons (indirect neurogenesis). The fate of RGCs is finely regulated during all the corticogenesis process and depends on time-scaled perception of external signals and expression of intrinsic factors. The present Review focuses on the role of physiological extracellular cues arising from the vicinity of neural progenitors on the regulation of dorsal neurogenesis and cerebral cortex patterning. It further discusses how pathogenic viral factors influence RGC behaviour and disrupt cerebral cortex development.

show abstract

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Cited by 101 publications

References 78 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

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

Cerebral cortex development: an outside‐in perspective

Contact Info

Product

Resources

About