Toll-like Receptor 3 Regulates Neural Stem Cell Proliferation by Modulating the Sonic Hedgehog Pathway

Yaddanapudi, Kavitha; Miranda, Joari De; Hornig, Mady; Lipkin, W. Ian

doi:10.1371/journal.pone.0026766

Cited by 26 publications

(16 citation statements)

References 70 publications

(75 reference statements)

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“…TLR3 has been linked to neurodegenerative disorders and negative regulation of axonogenesis, as well as dengue and ZIKV infection, so we hypothesized that ZIKV activates the TLR3 pathway in neural progenitor cells, thereby leading to pro-apoptotic pathway activation and/or dysregulation of cell fate decisions (Cameron et al, 2007; Hamel et al, 2015; Okun et al, 2010; Okun et al, 2011; Tsai et al, 2009; Yaddanapudi et al, 2011). As seen in microcephaly, dysregulated cell fate, self-renewal and apoptotic pathways in NPCs may contribute to the microcephaly phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…This temporally sensitive expression of TLR3 during early brain development may contribute to the trimester-specific response of fetal brains to ZIKV infection. Induction of TLR3 has been shown to trigger apoptosis by inhibiting Sonic Hedgehog and Ras-ERK signaling in NPCs and plays a role in retinopathy (Shiose et al, 2011; Yaddanapudi et al, 2011). Moreover, TLR3 has been connected to the elevated risk of neuropathological dysfunction resulting from maternal infection using TLR3-deficient mouse models (De Miranda et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

et al. 2016

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Emerging evidence from the current outbreak of Zika virus (ZIKV) indicates a strong causal link between Zika and microcephaly. To investigate how ZIKV infection leads to microcephaly, we used human embryonic stem cell-derived cerebral organoids to recapitulate early stage, first trimester fetal brain development. Here we show that a prototype strain of ZIKV MR766 efficiently infects organoids and causes a decrease in overall organoid size that correlates with the kinetics of viral copy number. The innate immune receptor Toll-Like-Receptor 3 (TLR3) was upregulated after ZIKV infection of human organoids and mouse neurospheres and TLR3 inhibition reduced the phenotypic effects of ZIKV infection. Pathway analysis of gene expression changes during TLR3 activation highlighted 41 genes also related to neuronal development, suggesting a mechanistic connection to disrupted neurogenesis. Together, therefore, our findings identify a link between ZIKV-mediated TLR3 activation, perturbed cell fate and a reduction in organoid volume reminiscent of microcephaly.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

et al. 2016

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“…NPCs also express TLRs 2, 3, and 4 and respond to TLR agonists, which regulate stem cell proliferation and differentiation, both in vitro and in vivo. While TLR 2 ligation stimulates neurogenesis (Rolls et al, 2007), TLR 3 and 4 downstream signaling has inhibitory effects on both stem cell proliferation and self-renewal (Rolls et al, 2007;Yaddanapudi et al, 2011), partly by inhibiting Sonic Hedgehog (Shh) signaling. Remarkably, the exposure to TLR 2 and 4 ligands induces the secretion of TNF-a by NPCs (Covacu et al, 2009) (Tables 1 and 2).…”

Section: Mscsmentioning

confidence: 99%

How stem cells speak with host immune cells in inflammatory brain diseases

Pluchino

Cossetti

2013

Glia

110

109

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Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.

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“…In mouse, Shh signaling regulates neural induction from ES cells (Cai et al, 2008) or NSCs (Dave et al, 2011). TLR3 regulates NSC proliferation by modulating Shh signaling (Yaddanapudi et al, 2011), perhaps through activation of NFκB (Kasperczyk et al, 2009). Many studies have demonstrated the importance of Wnt/β-catenin signaling in neurogenesis (Kondo et al, 2011; Pei et al, 2012) and its interaction with NFκB signaling in cancer stem cells (Gavert et al, 2011; Pan et al, 2012) and mesenchymal stem cells (Hyun Hwa et al, 2008; Kim et al, 2011b).…”

Section: Crosstalk Between Nfκb and Other Signaling Pathwaysmentioning

confidence: 99%

NFκB signaling regulates embryonic and adult neurogenesis

Zhang

2012

Front. Biol.

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Both embryonic and adult neurogenesis involves the self-renewal/proliferation, survival, migration and lineage differentiation of neural stem/progenitor cells. Such dynamic process is tightly regulated by intrinsic and extrinsic factors and complex signaling pathways. Misregulated neurogenesis contributes much to a large range of neurodevelopmental defects and neurodegenerative diseases. The signaling of NFκB regulates many genes important in inflammation, immunity, cell survival and neural plasticity. During neurogenesis, NFκB signaling mediates the effect of numerous niche factors such as cytokines, chemokines, growth factors, extracellular matrix molecules, but also crosstalks with other signaling pathways such as Notch, Shh, Wnt/β-catenin. This review summarizes current progress on the NFκB signaling in all aspects of neurogenesis, focusing on the novel role of NFκB signaling in initiating early neural differentiation of neural stem cells and embryonic stem cells.

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Toll-like Receptor 3 Regulates Neural Stem Cell Proliferation by Modulating the Sonic Hedgehog Pathway

Cited by 26 publications

References 70 publications

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

How stem cells speak with host immune cells in inflammatory brain diseases

NFκB signaling regulates embryonic and adult neurogenesis

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