scholarly journals Zika Virus Alters DNA Methylation of Neural Genes in an Organoid Model of the Developing Human Brain

mSystems ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Sylvie Janssens ◽  
Michael Schotsaert ◽  
Rahul Karnik ◽  
Vinod Balasubramaniam ◽  
Marion Dejosez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Zika Virus ◽  
Brain Disorders ◽  
Epigenetic Changes ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Neural Genes

Scientific research on human neural stem cells and cerebral organoids has confirmed the congenital neurotropic and neurodestructive nature of the Zika virus. However, the extent to which prenatal ZIKV infection is associated with more subtle brain alterations, such as epigenetic changes, remains ill defined. Here, we address the question of whether ZIKV infection induces DNA methylation changes with the potential to cause brain disorders later in life.

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons

2019 ◽  
Vol 13 ◽  
Author(s):  
Livia Rosa-Fernandes ◽  
Fernanda Rodrigues Cugola ◽  
Fabiele Baldino Russo ◽  
Rebeca Kawahara ◽  
Caio Cesar de Melo Freire ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Zika Virus ◽  
Human Neural Stem Cells

scholarly journals Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

2019 ◽  
Author(s):  
Jean A. Bernatchez ◽  
Michael Coste ◽  
Sungjun Beck ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Nucleoside Analogue ◽  
Zika Virus ◽  
Active Metabolite ◽  
Cytopathic Effect ◽  
Cell Model ◽  
Strong Activity ◽  
Human Neural Stem Cells ◽  
Neurodevelopmental Impairment

AbstractZika virus (ZIKV), an emerging flavivirus which causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome, continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Conversion of the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine to a 2-(methylthio)ethyl phosphoramidate completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. Molecular superpositioning revealed different orientations of residues opposite the 2′-fluoro group of sofosbuvir. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

scholarly journals p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Marin Navarro ◽  
Robin Johan Pronk ◽  
Astrid Tjitske van der Geest ◽  
Ganna Oliynyk ◽  
Ann Nordgren ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Genomic Stability ◽  
Neural Progenitors ◽  
Ips Cell ◽  
Human Neural Stem Cells ◽  
Neural Organization ◽  
Mature Neurons ◽  
Induced Pluripotent

AbstractIn this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate, downregulation of genes involved in oxidative phosphorylation (OXPHOS), and an upregulation of glycolytic capacity was apparent upon loss of p53. In addition, p53KD neural stem cells display an increased pace of differentiating into neurons and exhibit a phenotype corresponding to more mature neurons compared to control neurons. Using brain organoids, we modeled more specifically cortical neurogenesis. Here we found that p53 loss resulted in brain organoids with disorganized stem cell layer and reduced cortical progenitor cells and neurons. Similar to NES cells, neural progenitors isolated from brain organoids also show a downregulation in several OXPHOS genes. Taken together, this demonstrates an important role for p53 in controlling genomic stability of neural stem cells and regulation of neuronal differentiation, as well as maintaining structural organization and proper metabolic gene profile of neural progenitors in human brain organoids.

scholarly journals Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 365 ◽  
Author(s):  
Jean A. Bernatchez ◽  
Michael Coste ◽  
Sungjun Beck ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Nucleoside Analogue ◽  
Zika Virus ◽  
Active Metabolite ◽  
Cytopathic Effect ◽  
Cell Model ◽  
Strong Activity ◽  
Human Neural Stem Cells ◽  
Neurodevelopmental Impairment

Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

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