Luteolin Modulates Neural Stem Cells Fate Determination: In vitro Study on Human Neural Stem Cells, and in vivo Study on LPS-Induced Depression Mice Model

Luteolin is a natural flavone with neurotrophic effects observed on different neuronal cell lines. In the present study, we aimed to assess the effect of luteolin on hNSCs fate determination and the LPS-induced neuroinflammation in a mouse model of depression with astrocytogenesis defect. hNSCs were cultured in basal cell culture medium (control) or medium supplemented with luteolin or AICAR, a known inducer of astrogenesis. A whole-genome transcriptomic analysis showed that luteolin upregulated the expressions of genes related to neurotrophin, dopaminergic, hippo, and Wnt signaling pathways, and downregulated the genes involved in p53, TNF, FOXO, and Notch signaling pathways. We also found that astrocyte-specific gene GFAP, as well as other genes of the key signaling pathways involved in astrogenesis such as Wnt, BMP, and JAK-STAT pathways were upregulated in luteolin-treated hNSCs. On the other hand, neurogenesis and oligodendrogenesis-related genes, TUBB3, NEUROD 1 and 6, and MBP, were downregulated in luteolin-treated hNSCs. Furthermore, immunostaining showed that percentages of GFAP+ cells were significantly higher in luteolin- and AICAR-treated hNSCs compared to control hNSCs. Additionally, RT-qPCR results showed that luteolin upregulated the expressions of GFAP, BMP2, and STAT3, whereas the expression of TUBB3 remained unchanged. Next, we evaluated the effects of luteolin in LPS-induced mice model of depression that represents defects in astrocytogenesis. We found that oral administration of luteolin (10 mg/Kg) for eight consecutive days could decrease the immobility time on tail suspension test, a mouse behavioral test measuring depression-like behavior, and attenuate LPS-induced inflammatory responses by significantly decreasing IL-6 production in mice brain-derived astrocytes and serum, and TNFα and corticosterone levels in serum. Luteolin treatment also significantly increased mature BDNF, dopamine, and noradrenaline levels in the hypothalamus of LPS-induced depression mice. Though the behavioral effects of luteolin did not reach statistical significance, global gene expression analyses of mice hippocampus and brain-derived NSCs highlighted the modulatory effects of luteolin on different signaling pathways involved in the pathophysiology of depression. Altogether, our findings suggest an astrocytogenic potential of luteolin and its possible therapeutic benefits in neuroinflammatory and neurodegenerative diseases. However, further studies are required to identify the specific mechanism of action of luteolin.

Download Full-text

Safb1 regulates cell fate determination in adult neural stem cells by enhancing Drosha cleavage of NFIB mRNA

10.1101/2021.10.22.465432 ◽

2021 ◽

Author(s):

Nikolas Ifflander ◽

Chiara Rolando ◽

Elli-Anna Balta ◽

Pascal Forcella ◽

Tanzila Mukhtar ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Adult Brain ◽

Specific Gene ◽

Transcriptional Level ◽

Cell Fate Determination ◽

Fate Determination ◽

Attachment Factor ◽

Brain Homeostasis

During brain homeostasis, stem cell fate determination is crucial to guarantee function, adaptation and regeneration while preventing neurodegeneration and cognitive impairment. How neural stem cells (NSCs) are instructed to generate neurons or glia is not well understood. Here we addressed how fate is resolved in multipotent adult hippocampal NSCs, and identify Scaffold Attachment Factor B1 (Safb1) as a determinant of neuron production by blocking glial commitment. Safb1 is sufficient to block oligodendrocytic differentiation of NSCs by preventing expression of the transcription factor NFIB at the post-transcriptional level. Detailed interrogation of the Drosha interactome and functional validation revealed that Safb1 enhances NFIB mRNA cleavage in a Drosha-dependent fashion. Thus, our study provides a cellular mechanism for selective NSC fate regulation by post-transcriptional destabilization of mRNAs. Given the importance of NSC maintenance and fate determination in the adult brain, our findings have major implications for cell-specific gene expression, brain disease and aging.

Download Full-text

Mesenchymal stem cells regulate maintenance of neural stem cells through VEGFR2 and Notch signaling pathways

Cell Research ◽

10.1038/cr.2008.149 ◽

2008 ◽

Vol 18 (S1) ◽

pp. S59-S59

Author(s):

Zhifeng Deng ◽

Zhumin Liu ◽

Wei Tu ◽

Yang Wang ◽

Yuanlei Lou

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Neural Stem Cells ◽

Notch Signaling ◽

Signaling Pathways

Download Full-text

Signaling pathways of the early differentiation of neural stem cells by neurotrophin-3

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2007.04.045 ◽

2007 ◽

Vol 357 (4) ◽

pp. 903-909 ◽

Cited By ~ 34

Author(s):

Myung-Shin Lim ◽

Sang-Hyun Nam ◽

Sun-Jung Kim ◽

Seog-Youn Kang ◽

Yong-Soon Lee ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Signaling Pathways ◽

Early Differentiation ◽

Neurotrophin 3

Download Full-text

HBO Promotes the Differentiation of Neural Stem Cells via Interactions Between the Wnt3/β-Catenin and BMP2 Signaling Pathways

Cell Transplantation ◽

10.1177/0963689719883578 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1686-1699 ◽

Cited By ~ 2

Author(s):

Chongfeng Chen ◽

Yujia Yang ◽

Yue Yao

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Signaling Pathways ◽

System Development ◽

Nervous System Development ◽

Bmp Signaling ◽

Nuclear Proteins ◽

Therapeutic Effects ◽

Morphogenetic Protein

Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of Wnt3a, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of Wnt3a, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.

Download Full-text

Hyperthermia influences fate determination of neural stem cells with lncRNAs alterations in the early differentiation

PLoS ONE ◽

10.1371/journal.pone.0171359 ◽

2017 ◽

Vol 12 (2) ◽

pp. e0171359 ◽

Cited By ~ 3

Author(s):

Lei Wang ◽

Yujia Deng ◽

Da Duan ◽

Shuaiqi Sun ◽

Lite Ge ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Fate Determination ◽

Early Differentiation

Download Full-text

Protein signaling pathways in differentiation of neural stem cells

PROTEOMICS ◽

10.1002/pmic.200800096 ◽

2008 ◽

Vol 8 (21) ◽

pp. 4547-4559 ◽

Cited By ~ 15

Author(s):

Helena Skalnikova ◽

Petr Vodicka ◽

Steven Pelech ◽

Jan Motlik ◽

Suresh Jivan Gadher ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Signaling Pathways ◽

Protein Signaling

Download Full-text

Resolving the transcriptional transitions associated with oligodendrocyte generation from adult neural stem cells by single cell sequencing

10.1101/2020.12.18.423285 ◽

2020 ◽

Author(s):

Kasum Azim ◽

Filippo Calzolari ◽

Martina Cantone ◽

Rainer Akkermann ◽

Julio Vera ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Single Cell ◽

Signaling Pathways ◽

Regulatory Control ◽

Transcriptional Networks ◽

Detailed Knowledge ◽

List Type ◽

Specific Expression ◽

Gene Regulatory

AbstractThe subventricular zone (SVZ) is the largest neurogenic niche in the adult forebrain. Notably, neural stem cells (NSCs) of the SVZ generate not only neurons, but also oligodendrocytes, the myelin-forming cells of the central nervous system. Transcriptomic studies have provided detailed knowledge of the molecular events that regulate neurogenesis, but little is understood about adult oligodendrogenesis from SVZ-NSCs. To address this, we performed in-depth single-cell transcriptomic analyses to resolve the major differences in neuronal and oligodendroglial lineages derived from the adult SVZ. A hallmark of adult oligodendrogenesis was the stage-specific expression of transcriptional modulators that regulate developmental oligodendrogenesis. Notably, divergence of the oligodendroglial lineage was distinguished by Wnt-Notch and angiogenesis-related signaling, whereas G-protein-coupled receptor signaling pathways were the major signature observed in the neurogenic lineage. Moreover, in-depth gene regulatory network analysis identified key stage-specific master regulators of the oligodendrocyte lineage and revealed new mechanisms by which signaling pathways interact with transcriptional networks to control lineage progression. Our work provides an integrated view of the multi-step differentiation process leading from NSCs to mature oligodendrocytes, by linking environmental signals to known and novel transcriptional mechanisms orchestrating oligodendrogenesis.Main pointsDistinct adult NSC populations giving rise to either oligodendrocytes or neurons can be identified by the expression of transcription factors.Gene regulatory control of oligodendrogenesis is a major fate-determinant for their generation.

Download Full-text

Transient Induction of RET Activity Pushes CNS Neural Stem Cells Towards Enteric Phenotype Through Activation of Multiple Signaling Pathways

Gastroenterology ◽

10.1016/s0016-5085(11)60017-6 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-4

Author(s):

Gunjan Tiwari ◽

Maria-Adelaide Micci ◽

Subhash Kulkarni ◽

Laren Becker ◽

Johann Peterson ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Signaling Pathways ◽

Multiple Signaling

Download Full-text

Paracrine Neuroprotective Effects of Neural Stem Cells on Glutamate-Induced Cortical Neuronal Cell Excitotoxicity

Advanced Pharmaceutical Bulletin ◽

10.15171/apb.2015.070 ◽

2015 ◽

Vol 5 (4) ◽

pp. 515-521 ◽

Cited By ~ 5

Author(s):

Mohammad Hossein Geranmayeh ◽

Ali Baghbanzadeh ◽

Abbas Barin ◽

Jamileh Salar-Amoli ◽

Mohammad Mehdi Dehghan ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neuronal Cell ◽

Neuroprotective Effects

Download Full-text

Using Neural Stem Cells to Enhance Repair and Recovery of Spinal Circuits After Injury

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.218 ◽

2018 ◽

Author(s):

Itzhak Fischer ◽

Shaoping Hou

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

Early Stage ◽

Neuronal Cell ◽

Axon Growth ◽

Tumor Formation ◽

Term Survival ◽

Cord Injury

Spinal cord injury is characterized by a complex set of events, which include the disruption of connectivity between the brain and the periphery with little or no spontaneous regeneration, resulting in motor, sensory and autonomic deficits. Transplantation of neural stem cells has the potential to provide the cellular components for repair of spinal cord injury (SCI), including oligodendrocytes, astrocytes, and neurons. The ability to generate graft-derived neurons can be used to restore connectivity by formation of functional relays. The critical requirements for building a relay are to achieve long-term survival of graft-derived neurons and promote axon growth into and out of the transplant. Recent studies have demonstrated that mixed populations of glial and neuronal progenitors provide a permissive microenvironment for survival and differentiation of early-stage neurons, but inclusion of growth factors with the transplant or cues for directional axon growth outside the transplant may also be needed. Other important considerations include the timing of the transplantation and the selection of a population of neurons that maximizes the effective transmission of signals. In some experiments, the essential neuronal relay formation has been developed in both sensory and motor systems related to locomotion, respiration, and autonomic functions. Despite impressive advances, the poor regenerative capacity of adult CNS combined with the inhibitory environment of the injury remain a challenge for achieving functional connectivity via supraspinal tracts, but it is possible that recruitment of local propriospinal neurons may facilitate the formation of relays. Furthermore, it is clear that the new connections will not be identical to the original innervation, and therefore there needs to be a mechanism for translating the resulting connectivity into useful function. A promising strategy is to mimic the process of neural development by exploiting the remarkable plasticity associated with activity and exercise to prune and strengthen synaptic connections. In the meantime, the sources of neural cells for transplantation are rapidly expanding beyond the use of fetal CNS tissue and now include pluripotent ES and iPS cells as well as cells obtained by direct reprogramming. These new options can provide considerable advantages with respect to preparation of cell stocks and the use of autologous grafting, but they present challenges of complex differentiation protocols and risks of tumor formation. It is important to note that although neural stem cell transplantation into the injured spinal cord is primarily designed to provide preclinical data for the potential treatment of patients with SCI, it can also be used to develop analogous protocols for repair of neuronal circuits in other regions of the CNS damaged by injury or neurodegeneration. The advantages of the spinal cord system include well-defined structures and a large array of quantitative functional tests. Therefore, studying the formation of a functional relay will address the fundamental aspects of neuronal cell replacement without the additional complexities associated with brain circuits.

Download Full-text