TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases

Hiew, Lih-Fhung; Poon, Chi Him; You, Heng-Ze; Lim, Lee Wei

doi:10.3390/cells10061382

Cited by 43 publications

(36 citation statements)

References 158 publications

(183 reference statements)

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“…TGF-βs are a pleiotropic cytokines that are involved in regulating the growth and differentiation of various cells, immune regulation, and extracellular matrix metabolism ( Vivien and Ali, 2006 ; Dobolyi et al, 2012 ). TGF-βs elicit responses via interaction with TGF-β receptors and subsequent activation of Smad transcription factors ( Hiew et al, 2021 ). In the context of neurological disease, TGF-βs are sometimes shown to be neuroprotective and are downregulated in many models of neurological disease ( Tesseur et al, 2006 ; Vivien and Ali, 2006 ; Kashima and Hata, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Gage

Gard

Thippeswamy

2022

Front. Cell Dev. Biol.

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Glial scars have been observed following stab lesions in the spinal cord and brain but not observed and characterized in chemoconvulsant-induced epilepsy models. Epilepsy is a disorder characterized by spontaneous recurrent seizures and can be modeled in rodents. Diisopropylfluorophosphate (DFP) exposure, like other real-world organophosphate nerve agents (OPNAs) used in chemical warfare scenarios, can lead to the development of status epilepticus (SE). We have previously demonstrated that DFP-induced SE promotes epileptogenesis which is characterized by the development of spontaneous recurrent seizures (SRS), gliosis, and neurodegeneration. In this study, we report classical glial scars developed in the piriform cortex, but not in the hippocampus, by 8 days post-exposure. We challenged both male and female rats with 4–5 mg/kg DFP (s.c.) followed immediately by 2 mg/kg atropine sulfate (i.m.) and 25 mg/kg pralidoxime (i.m.) and one hour later by midazolam (i.m). Glial scars were present in the piriform cortex/amygdala region in 73% of the DFP treated animals. No scars were found in controls. Scars were characterized by a massive clustering of reactive microglia surrounded by hypertrophic reactive astrocytes. The core of the scars was filled with a significant increase of IBA1 and CD68 positive cells and a significant reduction in NeuN positive cells compared to the periphery of the scars. There was a significantly higher density of reactive GFAP, complement 3 (C3), and inducible nitric oxide synthase (iNOS) positive cells at the periphery of the scar compared to similar areas in controls. We found a significant increase in chondroitin sulfate proteoglycans (CS-56) in the periphery of the scars compared to a similar region in control brains. However, there was no change in TGF-β1 or TGF-β2 positive cells in or around the scars in DFP-exposed animals compared to controls. In contrast to stab-induced scars, we did not find fibroblasts (Thy1.1) in the scar core or periphery. There were sex differences with respect to the density of iNOS, CD68, NeuN, GFAP, C3 and CS-56 positive cells. This is the first report of cortical glial scars in rodents with systemic chemoconvulsant-induced SE. Further investigation could help to elucidate the mechanisms of scar development and mitigation strategies.

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Section: Discussionmentioning

confidence: 99%

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Gage

Gard

Thippeswamy

2022

Front. Cell Dev. Biol.

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“…The reduction in TGF-β signaling at an early stage of ALS is thought to block the neuroprotective effects of TGF-β, whereas at later stages of the disease, the over-activation of the TGF-β signaling promotes microglial activation and hence proinflammatory responses which cause further neurotoxicity ( Galbiati et al , 2020 ). Altogether, TGF-β signaling has a wide spectrum of roles in regulating the homeostasis of the nervous system ( Hiew et al , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

You

Cohen

Pustovalova

et al. 2022

Toxicological Sciences

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Elucidation of predictive fluidic biochemical markers to detect and monitor chemical-induced neurodegeneration has been a major challenge due to a lack of understanding of molecular mechanisms driving altered neuronal morphology and function, as well as poor sensitivity in methods to quantify low-level biomarkers in bodily fluids. Here, we evaluated five neurotoxicants (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, doxorubicin, paclitaxel, and rotenone) in human iPSC-derived neurons to profile secreted miRNAs at early and late stages of decline in neuronal cell morphology and viability. Based on evaluation of these morphological (neurite outgrowth parameters) and viability (ATP) changes, two concentrations of each chemical were selected for analysis in a human 754 miRNA panel: a low concentration with no/minimal effect on cell viability but a significant decrease in neurite outgrowth, and a high concentration with a significant decrease in both endpoints. A total of 39 miRNAs demonstrated significant changes (fold-change ≥1.5 or ≤ 0.67, p-value < 0.01) with at least one exposure. Further analyses of targets modulated by these miRNAs revealed 38 key mRNA targets with roles in neurological dysfunctions, and identified TGF-β signaling as a commonly enriched pathway. Of the 39 miRNAs, five miRNAs, three down-regulated (miR-20a, miR-30b, and miR-30d) and two up-regulated (miR-1243 and miR-1305), correlated well with morphological changes induced by multiple neurotoxicants and were notable based on their relationship to various neurodegenerative conditions and/or key pathways, such as TGF-β signaling. These data sets reveal miRNA candidates that warrant further evaluation as potential safety biomarkers of chemical-induced neurodegeneration.

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“…To further investigate the underlying mechanism of 1,25-dihydroxyvitamin D3 on brain injury of NPSLE, the key TGF-β/Smads signaling pathway was detected. TGF-β1 is implicated in a large number of interactions and plays a variety of roles according to the cellular environment (44). Firstly, TGF-β is one of the most important cytokines to activate and promote the transformation, exacerbating the process of in ammation (45).…”

Section: Discussionmentioning

confidence: 99%

“…And TGF-β is also associated with the immune dysregulation disorders such as Multiple Sclerosis (MS), in which a forceful increase in TGF-β expression and circulating TGF-β was observed during an MS attack in patients (46). Furthermore, TGF-β has been expressed in neural progenitor cells, differentiated neurons, and mature neural cells (19). In fact, TGF-β induces cell cycle exist the hippocampal neurons in mice (47) and is associated with the loss of adult neurogenesis by preventing the proliferation of progenitor cells (48).…”

Section: Discussionmentioning

confidence: 99%

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1,25-dihydroxyvitamin D3 attenuates NPSLE in MRL/lpr mice through a meliorating BCSFB activating PPARγ/NF-κB/TNF-α and lessening TGF-β 1/Smads

Liu

Zhao

et al. 2022

Preprint

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Backgrounds: Systemic lupus erythematosus encephalopathy (NPSLE) is a serious complication of systemic lupus erythematosus (SLE) involving the nervous system with high morbidity and mortality. A key hypothesis in NPSLE is that a disrupted barrier allowed autoantibodies and immune components of peripheral blood to penetrate into the central nervous system (CNS), resulting in inflammation and damage. The blood cerebrospinal fluid barrier (BCSFB), which consists of the choroid plexus and the hypothalamic tanycytes, has long been regarded as an immunological sanctuary site. 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is the active form of vitamin D, which plays multiple roles in inflammation and immunoregulation. In this study, we investigate the possible protective effects of 1,25-dihydroxyvitamin D3 on BCSFB dysfunction of NPSLE in MRL/lpr mice and explore the mechanism of 1,25-dihydroxyvitamin D3 inhibiting the progression of NPSLE.Methods：40 MRL/lpr mice at 11-week-old were included in this study and the mice were divided into VitD3-treated group and control group. Mice in the VitD3-treated groups received 4μg/kg 1,25-dihydroxyvitamin D3 in 1％ dimethyl sulfoxide（DMSO）intraperitoneal injection twice a week for 3 weeks. Mice in the control groups received 1% DMSO intraperitoneal injections for 3 weeks. The mice were anesthetized at 0 weeks (T1), 2 weeks (T2), 4 weeks (T3), and 6 weeks (T4) after treatment, and the mice were executed to collect blood and brain tissue samples. During this period, the skin lesions and neuropsychiatric manifestations of mice were observed continuously. The expressions of serum anti-double-stranded DNA (dsDNA) antibody and C3 complement were analyzed by ELISA. Then we evaluated the effect of 1,25-dihydroxyvitamin D3 on BCSFB integrity with time in terms of histopathological changes, neurological deficit, and the expression of brain-derived neurotrophic factor (BDNF) in MRL/lpr mice. BCSFB permeability and the expression of permeability-related proteins with time in the brain were also analyzed by immunofluorescence and western blotting respectively. To determine the possible mechanism underlying the role of 1,25-dihydroxyvitamin D3 in BCSFB maintenance, the effects of peroxisome proliferator-activated receptor-gamma (PPARγ) on BCSFB integrity and the expression of TGF-β/Smads on BCSFB integrity with time were detected.Results: The skin lesions, neuropsychiatric manifestations, and pathology of mice in the VitD3-treated group were significantly improved compared with those in the control group. The levels of A-dsDNA in the VitD3-treated group were significantly lower than those in the control group (P＜0.05). The C3 in the VitD3-treated group was significantly higher than those in the control group (P＜0.05). The expressions of occluding and claudin-2 in the VitD3-treated group were significantly higher than those in the control group (P＜0.05). 1,25-dihydroxyvitamin D3 treatment modulated the PPARγ/TNF-α/NF-κB axis and increased BDNF expression levels (P＜0.05). There were significant differences in TGF-β/Smads pathway expression between the two groups (P＜0.05). The TGF-β1, TβR-1, Smad2/3, and P-Smad2/3 in the VitD3-treated group were significantly lower than those in the control group (P＜0.05). Furthermore, these results presented the descending or increasing tendency in the VitD3-treated group or the control group.Conclusion: Our findings support the positive effect of 1,25-dihydroxyvitamin D3 on NPSLE in MRL/lpr mice, which may be related to the protection of BCSFB disruption through the activation of the anti-inflammatory PPARγ/NF-κB/TNF-α pathway as well as upregulation of BDNF and the inhibition of TGF-β/Smads signaling pathway.

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TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases

Cited by 43 publications

References 158 publications

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

1,25-dihydroxyvitamin D3 attenuates NPSLE in MRL/lpr mice through a meliorating BCSFB activating PPARγ/NF-κB/TNF-α and lessening TGF-β 1/Smads

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