Mid-pregnancy maternal immune activation increases Pax6-positive and Tbr2-positive neural progenitor cells and causes integrated stress response in the fetal brain in a mouse model of maternal viral infection

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). This link is particularly well established in the case of schizophrenia. Converging lines of evidence from human and animal model studies have suggested that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 hour) treatment with either interferon-gamma (IFNγ; 25 ng/μl) or interleukin (IL)-1β (10 ng/μl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Of these, 359 genes responded differently to IFNγ treatment in SZ relative to control lines, which were enriched for genes differentially expressed in adult SZ cases and in pathways related to the regulation of antigen processing, neuronal post-synaptic density, and the presynapse. There were no differentially expressed genes in the IL-1β-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1β impacts immune function and neuronal differentiation. Collectively, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to control NPCs; b) IL-1β may be less relevant to NPC cultures than IFNγ and c) the genes differentially regulated in schizophrenia lines are primarily mitochondrial, loss-of-function, pre- and post-synaptic genes. Our findings particularly highlight early synaptic development as a key target for future research into the mechanisms of association between maternal immune activation and schizophrenia risk.

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Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Journal of Virology ◽

10.1128/jvi.00351-15 ◽

2015 ◽

Vol 89 (13) ◽

pp. 6792-6804 ◽

Cited By ~ 19

Author(s):

Xiao-Jun Li ◽

Xi-Juan Liu ◽

Bo Yang ◽

Ya-Ru Fu ◽

Fei Zhao ◽

...

Keyword(s):

Stem Cell ◽

Notch Signaling ◽

Progenitor Cells ◽

Human Cytomegalovirus ◽

Neural Progenitor Cells ◽

Hcmv Infection ◽

Fetal Brain ◽

Neural Progenitor ◽

Notch Signaling Pathway ◽

Protein Levels

ABSTRACTHuman cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell developmentin vitro. Similar eventsin vivomay be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain.IMPORTANCECongenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.

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TNF-α Pretreatment Improves the Survival and Function of Transplanted Human Neural Progenitor Cells Following Hypoxic-Ischemic Brain Injury

Cells ◽

10.3390/cells9051195 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1195

Author(s):

Miri Kim ◽

Kwangsoo Jung ◽

Younhee Ko ◽

Il-Sun Kim ◽

Kyujin Hwang ◽

...

Keyword(s):

Brain Injury ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Infarct Volume ◽

Fetal Brain ◽

Neural Progenitor ◽

Great Promise ◽

Therapeutic Effects ◽

Ischemic Brain ◽

Tnf Α

Neural progenitor cells (NPCs) therapy offers great promise in hypoxic-ischemic (HI) brain injury. However, the poor survival of implanted NPCs in the HI host environment limits their therapeutic effects. Tumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that is induced in response to a variety of pathological processes including inflammation and immunity. On the other hand, TNF-α has protective effects on cell apoptosis and death and affects the differentiation, proliferation, and survival of neural stem/progenitor cells in the brain. The present study investigated whether TNF-α pretreatment on human NPCs (hNPCs) enhances the effectiveness of cell transplantation therapy under ischemic brain. Fetal brain tissue-derived hNPCs were pretreated with TNF-α before being used in vitro experiments or transplantation. TNF-α significantly increased expression of cIAP2, and the use of short hairpin RNA-mediated knockdown of cIAP2 demonstrated that cIAP2 protected hNPCs against HI-induced cytotoxicity. In addition, pretreatment of hNPCs with TNF-α mediated neuroprotection by altering microglia polarization via increased expression of CX3CL1 and by enhancing expression of neurotrophic factors. Furthermore, transplantation of TNF-α-treated hNPCs reduced infarct volume and improved neurological functions in comparison with non-pretreated hNPCs or vehicle. These findings show that TNF-α pretreatment, which protects hNPCs from HI-injured brain-induced apoptosis and increases neuroprotection, is a simple and safe approach to improve the survival of transplanted hNPCs and the therapeutic efficacy of hNPCs in HI brain injury.

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In Vitro Zika Virus Infection of Human Neural Progenitor Cells: Meta-Analysis of RNA-Seq Assays

Microorganisms ◽

10.3390/microorganisms8020270 ◽

2020 ◽

Vol 8 (2) ◽

pp. 270 ◽

Cited By ~ 3

Author(s):

Rossella Gratton ◽

Paola Maura Tricarico ◽

Almerinda Agrelli ◽

Heverton Valentim Colaço da Silva ◽

Lucas Coêlho Bernardo ◽

...

Keyword(s):

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Meta Analysis ◽

Fetal Brain ◽

Neural Progenitor ◽

Gene Expression Omnibus ◽

Human Neural Progenitor Cells ◽

Apoptosis Pathways

The Zika virus (ZIKV) is an emergent arthropod-borne virus (arbovirus) responsible for congenital Zika syndrome (CZS) and a range of other congenital malformations. Evidence shows that ZIKV infects human neural progenitor cells (hNPCs) in the fetal brain, prompting inflammation and tissue damage/loss. Despite recent advances, little is known about the pathways involved in CZS pathogenesis. We performed a meta-analysis, gene ontology (GO), and pathway analysis of whole transcriptome studies with the aim of clarifying the genes and pathways potentially altered during hNPCs infection with ZIKV. We selected three studies (17 samples of infected hPNCs compared to hPNCs uninfected controls) through a systematic search of the Gene Expression Omnibus (GEO) database. The raw reads were trimmed, counted, and normalized. Next, we performed a rank product meta-analysis to detect consistently differentially expressed genes (DEGs) in these independent experiments. We detected 13 statistically significant DEGs. GO ontology and reactome analysis showed an enrichment of interferon, pro-inflammatory, and chemokines signaling and apoptosis pathways in ZIKV-infected cells. Moreover, we detected three possible new candidate genes involved in hNPCs infection: APOL6, XAF1, and TNFRSF1. Our results confirm that interferon (IFN) signaling dominates the ZIKV response, and that a crucial contribution is given by apoptotic pathways, which might elicit the CZS phenotype.

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Mouse neural progenitor cells differentiate into oligodendrocytes in the brain of a knockout mouse model of Canavan disease

Developmental Brain Research ◽

10.1016/j.devbrainres.2004.07.003 ◽

2004 ◽

Vol 153 (1) ◽

pp. 19-27 ◽

Cited By ~ 17

Author(s):

Sankar Surendran ◽

Lamya S. Shihabuddin ◽

Jennifer Clarke ◽

Tatyana V. Taksir ◽

Gregory R. Stewart ◽

...

Keyword(s):

Mouse Model ◽

Progenitor Cells ◽

Knockout Mouse ◽

Neural Progenitor Cells ◽

Canavan Disease ◽

Neural Progenitor ◽

Knockout Mouse Model ◽

The Brain

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Modulating cognitive deficits and tau accumulation in a mouse model of aging Down syndrome through neonatal implantation of neural progenitor cells

Experimental Gerontology ◽

10.1016/j.exger.2012.06.013 ◽

2012 ◽

Vol 47 (9) ◽

pp. 723-733 ◽

Cited By ~ 9

Author(s):

Angela L. Rachubinski ◽

Kenneth N. Maclean ◽

Jeffrey R. Evans ◽

Kimberly B. Bjugstad

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Progenitor Cells ◽

Cognitive Deficits ◽

Neural Progenitor Cells ◽

Neural Progenitor

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Feline Neural Progenitor Cells I: Long-Term Expansion under Defined Culture Conditions

Stem Cells International ◽

10.1155/2012/108340 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Jing Yang ◽

Jinmei Wang ◽

Ping Gu ◽

X. Joann You ◽

Henry Klassen

Keyword(s):

Progenitor Cells ◽

Neural Progenitor Cells ◽

Primary Cultures ◽

Fetal Brain ◽

Neural Progenitor ◽

Time Frame ◽

Culture Conditions ◽

Defined Culture ◽

Transplantation Experiments

Neural progenitor cells (NPCs) of feline origin (cNPCs) have demonstrated utility in transplantation experiments, yet are difficult to grow in culture beyond the 1 month time frame. Here we use an enriched, serum-free base medium (Ultraculture) and report the successful long-term propagation of these cells. Primary cultures were derived from fetal brain tissue and passaged in DMEM/F12-based or Ultraculture-based proliferation media, both in the presence of EGF + bFGF. Cells in standard DMEM/F12-based medium ceased to proliferate by 1-month, whereas the cells in the Ultraculture-based medium continued to grow for at least 5 months (end of study) with no evidence of senescence. The Ultraculture-based cultures expressed lower levels of progenitor and lineage-associated markers under proliferation conditions but retained multipotency as evidenced by the ability to differentiate into neurons and glia following growth factor removal in the presence of FBS. Importantly, later passage cNPCs did not develop chromosomal aberrations.

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