Migration Of Neural Stem Cells Research Articles

Transitions in development – an interview with Rosa Uribe

Rosa Uribe is an Assistant Professor of BioSciences at Rice University. Having established her lab in 2017, her research focusses on identifying the genetic, cellular and signalling-level mechanisms of neural crest stem cell proliferation, migration and differentiation during embryogenesis. We caught up with Rosa to find out more about her career, her opinions about mentorship and a series of virtual seminars that she co-organises.

Hypoxic postconditioning promotes neurogenesis by modulating the metabolism of neural stem cells after cerebral ischemia

Ischemic stroke is one of the most lethal and severely disabling diseases that seriously affects human health and quality of life. The maintenance of self-renewal and differentiation of neural stem cells are closely related to metabolism. This study aimed to investigate whether hypoxic postconditioning (HPC) could promote neurogenesis after ischemic stroke, and to investigate the role of neuronal stem cell metabolism in HPC-induced neuroprotection. Male C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO), and HPC was performed for 3 h per day. Immunofluorescence staining was used to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 21% O2 or 8% O2. HPC promoted the recovery of neurological function in mice on day 14. HPC promoted neuronal precursor proliferation in the subventricular zone (SVZ) on day 7 and enhanced neuronal precursor migration in the basal ganglia and cortex on day 14. Fatty acid oxidation (FAO) and glycolysis of neural stem cells in the SVZ changed after MCAO with or without HPC. HPC promoted the proliferation of NE-4C stem cells, decreased FAO and increased glycolysis. All these beneficial effects of HPC were ablated by the application of an FAO activator or a glycolysis inhibitor. In conclusion, cerebral ischemia modulated the FAO and glycolysis of neural stem cells. HPC promoted the proliferation and migration of neural stem cells after MCAO, and these effects may be related to the regulation of metabolism, including FAO and glycolysis.

Neural stem cell treatment for perinatal brain injury: A systematic review and meta-analysis of preclinical studies.

Perinatal brain injury can lead to significant neurological and cognitive deficits and currently no therapies can regenerate the damaged brain. Neural stem cells (NSCs) have the potential to engraft and regenerate damaged brain tissue. The aim of this systematic review was to evaluate the preclinical literature to determine whether NSC administration is more effective than controls in decreasing perinatal brain injury. Controlled interventional studies of NSC therapy using animal models of perinatal brain injury were identified using MEDLINE and Embase. Primary outcomes were brain infarct size, motor, and cognitive function. Data for meta‐analysis were synthesized and expressed as standardized mean difference (SMD) with 95% confidence intervals (CI), using a random effects model. We also reported secondary outcomes including NSC survival, migration, differentiation, and effect on neuroinflammation. Eighteen studies met inclusion criteria. NSC administration decreased infarct size (SMD 1.09; CI: 0.44, 1.74, P = .001; I 2 = 74%) improved motor function measured via the impaired forelimb preference test (SMD 2.27; CI: 0.85, 3.69, P = .002; I 2 = 86%) and the rotarod test (SMD 1.88; CI: 0.09, 3.67, P = .04; I 2 = 95%). Additionally, NSCs improved cognitive function measured via the Morris water maze test (SMD of 2.41; CI: 1.16, 3.66, P = .0002; I 2 = 81%). Preclinical evidence suggests that NSC therapy is promising for the treatment of perinatal brain injury. We have identified key knowledge gaps, including the lack of large animal studies and uncertainty regarding the necessity of immunosuppression for NSC transplantation in neonates. These knowledge gaps should be addressed before NSC treatment can effectively progress to clinical trial.

Microneedle-mediated vascular endothelial growth factor delivery promotes angiogenesis and functional recovery after stroke

Ischemic stroke is still the major cause of disability worldwide. Although vascular endothelial growth factor (VEGF) is able to promote both angiogenesis and functional recovery, its use is limited by needle-induced injury, nonhomogenous VEGF distribution, and limited VEGF retention in the brain after intracranial or intravenous injection. Here, we first present a gelatin methacryloyl (GelMA) microneedle (MN)-based platform for the sustained and controlled local delivery of an adeno-associated virus (AAV) expressing human VEGF (AAV-VEGF) that achieves homogenous distribution and high transfection efficiency in ischemic brains. An ischemic stroke model was established in adult rats, and MNs loaded with AAV-VEGF were epicortically inserted into both the ischemic core and penumbra of these rats one day after the onset of ischemia. One week later, the inflammatory response and microneedle biocompatibility were assessed by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. Eight weeks later, angiogenesis and neural stem cell proliferation and migration were assessed. GelMA MN implantation did not elicit an obvious inflammatory response and had good biocompatibility in the brain. AAV–green fluorescent protein (GFP)-loaded MNs could achieve successful transfection and homogeneous distribution in the brain cortex three weeks postoperatively. MNs loaded with AAV-VEGF increased VEGF expression and enhanced functional angiogenesis and neurogenesis. In summary, MNs might emerge as a promising platform for delivering various therapeutics to treat ischemic stroke and repair other neurologically diseased tissues.

Repetitive transcranial magnetic stimulation increases neurological function and endogenous neural stem cell migration via the SDF-1α/CXCR4 axis after cerebral infarction in rats.

Neural stem cell (NSC) migration is closely associated with brain development and is reportedly involved during recovery from ischaemic stroke. Chemokine signalling mediated by stromal cell-derived factor 1α (SDF-1α) and its receptor CXC chemokine receptor 4 (CXCR4) has been previously documented to guide the migration of NSCs. Although repetitive transcranial magnetic stimulation (rTMS) can increase neurological function in a rat stroke model, its effects on the migration of NSCs and associated underlying mechanism remain unclear. Therefore, the present study investigated the effects of rTMS on ischaemic stroke following middle cerebral artery occlusion (MCAO). All rats underwent rTMS treatment 24 h after MCAO. Neurological function, using modified Neurological Severity Scores and grip strength test and NSC migration, which were measured using immunofluorescence staining, were analysed at 7 and 14 days after MCAO, before the protein expression levels of the SDF-1α/CXCR4 axis was evaluated using western blot analysis. AMD3100, a CXCR4 inhibitor, was used to assess the effects of SDF-1α/CXCR4 signalling. In addition, neuronal survival was investigated using Nissl staining at 14 days after MCAO. It was revealed that rTMS increased the neurological recovery of rats with MCAO, facilitated the migration of NSC, augmented the expression levels of the SDF-1α/CXCR4 axis and decreased neuronal loss. Furthermore, the rTMS-induced positive responses were significantly abolished by AMD3100. Overall, these results indicated that rTMS conferred therapeutic neuroprotective properties, which can restore neurological function after ischaemic stroke, in a manner that may be associated with the activation of the SDF-1α/CXCR4 axis.

Icariin Promotes Survival, Proliferation, and Differentiation of Neural Stem Cells In Vitro and in a Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) involves the degeneration of cholinergic neurons in the basal forebrain. Neural stem cell (NSC) transplantation has emerged as a promising therapeutic approach for treating AD. Icariin (ICA) is the main active component in Epimedium, a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of ICA on the proliferation and differentiation of NSCs in the basal forebrain of a fimbria-fornix transection (FFT) rat model. In the present study, ICA promoted the survival, proliferation, and migration of NSCs in vitro. In FFT rats, ICA promoted the proliferation and differentiation of NSCs into neurons and increased the number of cholinergic neurons in the MS and VDB of the basal forebrain. These results suggest that combination therapy of ICA oral administration and NSC transplantation may provide a new potential and effective approach for AD therapy.

Orexin-A Attenuates Inflammatory Responses in Lipopolysaccharide-Induced Neural Stem Cells by Regulating NF-KB and Phosphorylation of MAPK/P38/Erk Pathways.

BackgroundNeuronal damage is the main cause of neurological diseases. Neural stem cells (NSCs) have the functions of cell repair and replacement of neurons, secretion of neurotrophic factors, and immune regulation of the neural microenvironment.ObjectivePrevious study found that Orexin-A had a protective effect on neurons in the central nervous system, but it is lacking in making great efforts on the function of Orexin-A on NSCs. This study aimed to investigate the anti-inflammatory responses and signaling mechanisms of Orexin-A on lipopolysaccharide (LPS)-induced NSCs.MethodsQuantitative real-time polymerase chain reaction was used to detect the mRNA level. Signaling pathway-related protein expression was detected by Western blot. The proliferation and migration of NSCs were investigated by Cell Counting Kit-8 (CCK-8) detection kit and transwell assay. Besides, the staining of hematoxylin and eosin (HE) was performed to study the morphology of cell.ResultsOrexin-A decreased the pro-inflammatory cytokines of IL-1β, TNF-α, and IL-6 induced by LPS by regulating nuclear factor-k-gene binding (NF-kB) and phosphorylation of P38/Erk-mitogen-activated protein kinases (MAPKs) pathways, but not p-JNK signaling.ConclusionOur findings indicate that Orexin-A can alleviate the inflammatory response of NSC. It can provide beneficial help in neural stem cell therapy applications.

Https://iupress.istanbul.edu.tr/en/journal/experimed/article/yetiskin-norogenez-ve-norodejeneratif-hastaliklarda-buyume-faktorlerinin-rolu

Neurogenesis is the combined processes of division, migration and differentiation of neural stem cells (NSCs). The two different locations: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) in the hippocampus dentate gyrus (DG), provide a niche environment for neurogenesis. Neurotrophic factors have roles on migration, proliferation and differentiation of NSC and neural progenitor cells. Studies have shown that NSCs have regulatory effects on neural cell rearrangement, neural plasticity and angiogenesis in damaged tissue. In adult neurogenesis, combinations of neurotrophic factors play an important role in the treatment of cerebrovascular, neurodegenerative, oncological diseases and post-traumatic inflammatory damage. In this review, current literature including pre-clinical and clinical studies for the modulating effect of neurotrophic factors on NSCs and their potential therapeutic treatment applications are brought together. It contains up-to-date information that would be beneficial for researchers and physicians working in this field.

Tailoring Nano-Porous Surface of Aligned Electrospun Poly (L-Lactic Acid) Fibers for Nerve Tissue Engineering.

Despite the existence of many attempts at nerve tissue engineering, there is no ideal strategy to date for effectively treating defective peripheral nerve tissue. In the present study, well-aligned poly (L-lactic acid) (PLLA) nanofibers with varied nano-porous surface structures were designed within different ambient humidity levels using the stable jet electrospinning (SJES) technique. Nanofibers have the capacity to inhibit bacterial adhesion, especially with respect to Staphylococcus aureus (S. aureus). It was noteworthy to find that the large nano-porous fibers were less detrimentally affected by S. aureus than smaller fibers. Large nano-pores furthermore proved more conducive to the proliferation and differentiation of neural stem cells (NSCs), while small nano-pores were more beneficial to NSC migration. Thus, this study concluded that well-aligned fibers with varied nano-porous surface structures could reduce bacterial colonization and enhance cellular responses, which could be used as promising material in tissue engineering, especially for neuro-regeneration.

4D spatiotemporal modulation of biomolecules distribution in anisotropic corrugated microwrinkles via electrically manipulated microcapsules within hierarchical hydrogel for spinal cord regeneration

Although traditional 3D scaffolds or biomimetic hydrogels have been used for tissue engineering and regenerative medicine, soft tissue microenvironment usually has a highly anisotropic structure and a dynamically controllable deformation with various biomolecule distribution. In this study, we developed a hierarchical hybrid gelatin methacrylate-microcapsule hydrogel (HGMH) with Neurotrophin-3(NT-3)-loaded PLGA microcapsules to fabricate anisotropic structure with patterned NT-3 distribution (demonstrated as striped and triangular patterns) by dielectrophoresis (DEP). The HGMH provides a dynamic biomimetic sinuate-microwrinkles change with NT-3 spatial gradient and 2-stage time-dependent distribution, which was further simulated using a 3D finite element model. As demonstrated, in comparison with striped-patterned hydrogel, the triangular-patterned HGMH with highly anisotropic array of microcapsules exhibits remarkably spatial NT-3 gradient distributions that can not only guide neural stem cells (NSCs) migration but also facilitate spinal cord injury regeneration. This approach to construct hierarchical 4D hydrogel system via an electromicrofluidic platform demonstrates the potential for building various biomimetic soft scaffolds in vitro tailed to real soft tissues.

In vitro investigation of growth factors including MGF and IGF-1 in neural stem cell activation, proliferation, and migration

Neurogenesis is mainly activated after damage in adult tissues. This destruction activates the neural stem cells (NSCs) by exiting from a quiescent state and initiating proliferation, differentiation, and migration towards the damaged area. Although studies have investigated to clarify the process of NSC biology and neurogenesis, there are still significant artifacts in understanding the primary mechanism. It is known that only a small percentage of NSC become neurons and integrate into the brain tissue after this process. The significant proportion differentiates to become either astrocytes or oligodendrocytes. Furthermore, the quiescent stem cells in the niche are mainly activated by the stimuli affect. In recent years, many studies have been conducted with varying hormones, some of which might provide neuro-stimulation effect and/or involved in the regeneration of the brain tissue and/or neuroprotection from traumatic or ischemic pathologies, including Insulin-like growth factor 1 (IGF-1), Mechano Growth Factor (MGF), Basic Fibroblast Growth Factor (FGF-2), Erythropoietin (EPO), Epidermal Growth Factor (EGF), Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF).In this study, we examined the effects of FGF-2, MGF, IGF-1, EPO, EGF, NGF, and BDNF alone or with various combinations on rat hippocampal NSC by tracking the changes in the expression of Nestin, GFAP, TUBB3, and DCX genes during 24 h (h), 72 h and 168 h time frame. The apoptosis analysis revealed that FGF-2 and FGF-2 coupled growth factors effectively protect NSCs against apoptosis, whereas MGF coupled growth factors failed in this protection. The cell cycle analysis demonstrated that these growth factors had accumulated the NSCs exit from the quiescent phase to the Mitosis phase, mostly without being long in the Synthesis Phase. Neurosphere sizes were increased with MGF, signifying MGF being effective in neural progenitor cells. The combined use of MGF with FGF-2 was more effective in postmitotic neurons than MGF alone.We have comparatively demonstrated the effect of cytokines alone and combined administration on activation, proliferation, and migration of NSCs. Although many issues are still waiting to be investigated in adult neurogenesis, neural regeneration, and adult neural stem cell biology, the results provide vital resources to the researchers that are interested in the varying effect of growth factor on NSC.

Immunomodulatory Layered Double Hydroxide Nanoparticles Enable Neurogenesis by Targeting Transforming Growth Factor-β Receptor 2.

Immune microenvironment amelioration and reconstruction by functional biomaterials has become a promising strategy for spinal cord injury (SCI) recovery. In this study, we evaluated the neural regeneration and immunoregulation functions of Mg/Al layered double hydroxide (Mg/Al-LDH) nanoparticles in completely transected and excised mice and revealed the immune-related mechanisms. LDH achieved significant performance in accelerating neural stem cells (NSCs) migration, neural differentiation, L-Ca2+ channel activation, and inducible action potential generation. In vivo, the behavioral and electrophysiological performance of SCI mice was significantly improved by LDH implantation, with BrdU+ endogenous NSCs and neurons clearly observed in the lesion sites. According to RNA-seq and ingenuity pathway analysis, transforming growth factor-β receptor 2 (TGFBR2) is the key gene through which LDH inhibits inflammatory responses and accelerates neural regeneration. Significant colocalization of TGFBR2 and LDH was found on the cell membranes of NSCs both in vitro and in vivo, and LDH increased the expression of TGF-β2 in NSCs and activated the proliferation of precursor neural cells. LDH decreased the expression of M1 markers and increased the expression of M2 markers in both microglia and bone marrow-derived macrophages, and these effects were reversed by a TGFBR2 inhibitor. In addition, as a carrier, LDH loaded with NT3 exhibited better recovery effects with regard to the basso mouse scale score, motor evoked potential performance, and regenerated neural cell numbers than LDH itself. Thus, we have developed Mg/Al-LDH that can be used to construct a suitable immune microenvironment for SCI recovery and have revealed the targeted receptor.

NSCs Migration Promoted and Drug Delivered Exosomes-Collagen Scaffold via a Bio-Specific Peptide for One-Step Spinal Cord Injury Repair.

Spinal cord injury (SCI) is plaguing medical professionals globally due to the complexity of injury progression. Based on tissue engineering technology, there recently emerges a promising way by integrating drugs with suitable scaffold biomaterials to mediate endogenous neural stem cells (NSCs) to achieve one-step SCI repair. Herein, exosomes extracted from human umbilical cord-derived mesenchymal stem cells (MExos) are found to promote the migration of NSCs in vitro/in vivo. Utilizing MExos as drug delivery vehicles, a NSCs migration promoted and paclitaxel (PTX) delivered MExos-collagen scaffold is designed via a novel dual bio-specificity peptide (BSP) to effectively retain MExos within scaffolds. By virtue of the synergy that MExos recruit endogenous NSCs to the injured site, and PTX induce NSCs to give rise to neurons, this multifunctional scaffold has shown superior performance for motor functional recovery after complete SCI in rats by enhancing neural regeneration and reducing scar deposition. Besides, the dual bio-specific peptide demonstrates the capacity of tethering other cells-derived exosomes on collagen scaffold, such as erythrocytes-derived or NSCs-derived exosomes on collagen fibers or membranes. The resulting exosomes-collagen scaffold may serve as a potential multifunctional therapy modality for various disease treatments including SCI.

3D Printed Hydrogels with Aligned Microchannels to Guide Neural Stem Cell Migration.

Following traumatic or ischemic brain injury, rapid cell death and extracellular matrix degradation lead to the formation of a cavity at the brain lesion site, which is responsible for prolonged neurological deficits and permanent disability. Transplantation of neural stem/progenitor cells (NSCs) represents a promising strategy for reconstructing the lesion cavity and promoting tissue regeneration. In particular, the promotion of neuronal migration, organization, and integration of transplanted NSCs is critical to the success of stem cell-based therapy. This is particularly important for the cerebral cortex, the most common area involved in brain injuries, because the highly organized structure of the cerebral cortex is essential to its function. Biomaterials-based strategies show some promise for conditioning the lesion site microenvironment to support transplanted stem cells, but the progress in demonstrating organized cell engraftment and integration into the brain is very limited. An effective approach to sufficiently address these challenges has not yet been developed. Here, we have implemented a digital light-processing-based 3D printer and printed hydrogel scaffolds with a designed shape, uniaxially aligned microchannels, and tunable mechanical properties. We demonstrated the capacity to achieve high shape precision to the lesion site with brain tissue-matching mechanical properties. We also established spatial control of bioactive molecule distribution within 3D printed hydrogel scaffolds. These printed hydrogel scaffolds have shown high neuro-compatibility with aligned neuronal outgrowth along with the microchannels. This study will provide a biomaterial-based approach that can serve as a protective and guidance vehicle for transplanted NSC organization and integration for brain tissue regeneration after injuries.

Endothelial cell secreted metalloproteinase-2 enhances neural stem cell N-cadherin expression, clustering, and migration.

Neuroblasts have a clustered phenotype critical for their unidirectional migration, which in part is dependent on signaling from microvascular endothelial cells (EC) and pericytes (PC). Diffusible signals secreted by vascular cells have been demonstrated to increase survival, proliferation, and differentiation of subventricular zone resident neural stem cells (NSC); however, the signals that promote the necessary initiating step of NSC clustering are undefined. To investigate the role of vascular cells in promoting NSC clustering and directing migration, we created a 3-D hydrogel that mimics the biomechanics, biochemistry, and architectural complexity of brain tissue. We demonstrate that EC, and not PC, have a crucial role in NSC clustering and migration, further verified through microfluidic chamber systems and traction force microscopy. Ablation of the extended NSC aggregate arm halts aggregate movement, suggesting that clustering is a prerequisite for migration. When cultured with EC, NSC clustering occurs and NSC coincidentally increase their expression of N-cadherin, as compared to NSC cultured alone. NSC-presented N-cadherin expression was increased following exposure to EC secreted metalloproteinase-2 (MMP2). We demonstrate that inhibition of MMP2 prevented NSC N-cadherin surface expression and subsequent NSC clustering, even when NSC were in direct contact with EC. Furthermore, with exogenous activation of EGFR, which serves as a downstream activator of N-cadherin cleavage, NSC form clusters. Our results suggest that EC secretion of MMP2 promotes NSC clustering through N-cadherin expression. The insight gained about the mechanisms by which EC promote NSC migration may enhance NSC therapeutic response to sites of injury.

Decellularized optic nerve functional scaffold transplant facilitates directional axon regeneration and remyelination in the injured white matter of the rat spinal cord

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury. However, achieving good outcome remains difficult. Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites. However, it has not been reported whether this material promotes axonal regeneration in vivo. In the present study, a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells. This functional scaffold promoted the directional growth and remyelination of regenerating axons. In vitro, the porcine decellularized optic nerve contained many straight, longitudinal channels with a uniform distribution, and microscopic pores were present in the channel wall. The spatial micro topological structure and extracellular matrix were conducive to the adhesion, survival and migration of neural stem cells. The scaffold promoted the directional growth of dorsal root ganglion neurites, and showed strong potential for myelin regeneration. Furthermore, we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo. Four weeks later, the regenerating axons grew straight, the myelin sheath in the injured/transplanted area recovered its structure, and simultaneously, the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced. Together, these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration. All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2019-B034) on February 28, 2019.

Curcumin promotes the proliferation, invasion of neural stem cells and formation of neurospheres via activating SDF-1/CXCR4 axis.

Curcumin is an active ingredient isolated from the rhizomes of Curcuma longa Linn with remarkably non-toxic bioavailability. This is an in vitro study. In this study, we explored the effects of curcumin on the proliferation, migration and neurogenesis of neural stem cells (NSCs). Primary NSCs were isolated from embryonic day 14 rats and then treated with curcumin and/or stromal derived factor-1 (SDF-1). NSCs showed an SDF-1-dependent proliferation and migration. Further results showed that curcumin and SDF-1 both promoted NSCs proliferation, migration and the formation of neurospheres. In addition, Curcumin up-regulated the expression of SDF-1 and promoted the formation of SDF-1/CXCR4 complex in NSCs. The western blot results showed that the phosphorylation levels of ERK, JNK, MAPK, NF-kB and Akt were up-regulated by curcumin. In contrast, the administration of CXCR4 inhibitor AMD3100 could offset the effect of curcumin. These results suggested that curcumin promoted the NSCs proliferation, migration and formation of neurospheres via SDF-1/CXCR4 in NSCs.

The neurosphere assay: an effective in vitro technique to study neural stem cells.

The neurosphere assay: an effective in vitro technique to study neural stem cells.

5,6,7,4'-Tetramethoxyflavanone alleviates neurodegeneration in a dexamethasone-induced neurodegenerative mouse model through promotion of neurogenesis via the Raf/ERK1/2 pathway.

Adult neurogenesis plays an important role in improving cognitive functions. Neurogenesis generates new neurons, a process mediated by neural stem cell proliferation, migration, and differentiation. Long-term exposure to high levels of glucocorticoid results in the suppression of neurogenesis pathways and leads to the onset of cognitive impairment. The induction of neurogenesis by a potent bioactive compound is considered the most promising treatment for neurodegenerative disorders. 5,6,7,4'-Tetramethoxyflavanone (TMF) is a flavonoid compound isolated from Chromolaena odorata (L.) R. M. King & H. Rob. Previous study showed that TMF improved cognitive impairment by attenuating Aβ production and pTau expression, thereby increased cell survival and promoted synaptic plasticity. The aim of this study was to investigate the effect of TMF on dexamethasone (DEX)-suppressed neurogenesis in mice. Mice received DEX for 28 days before being treated with TMF for additional 30 days. Mice were randomly divided into four groups: control, TMF, DEX, and DEX + TMF. TMF promoted neurogenesis by increasing BrdU-positive cells, Prox1, doublecortin, and Nestin expression. TMF also upregulated the expression of Raf and extracellular-signal-regulated kinase (ERK)1/2, which are pivotal for neurogenesis signaling. In conclusion, TMF promoted neurogenesis-related protein expression in the proliferation, differentiation, and maturation phases via Raf/ERK1/2 signaling pathway.

Neuronal Hippo signaling: From development to diseases.

Hippo signaling pathway is a highly conserved and familiar tissue growth regulator, primarily dealing with cell survival, cell proliferation, and apoptosis. The Yes-associated protein (YAP) is the key transcriptional effector molecule, which is under negative regulation of the Hippo pathway. Wealth of studies have identified crucial roles of Hippo/YAP signaling pathway during the process of development, including the development of neuronal system. We provide here, an overview of the contributions of this signaling pathway at multiple stages of neuronal development including, proliferation of neural stem cells (NSCs), migration of NSCs toward their destined niche, maintaining NSCs in the quiescent state, differentiation of NSCs into neurons, neuritogenesis, synaptogenesis, brain development, and in neuronal apoptosis. Hyperactivation of the neuronal Hippo pathway can also lead to a variety of devastating neurodegenerative diseases. Instances of aberrant Hippo pathway leading to neurodegenerative diseases along with the approaches utilizing this pathway as molecular targets for therapeutics has been highlighted in this review. Recent evidences suggesting neuronal repair and regenerative potential of this pathway has also been pointed out, that will shed light on a novel aspect of Hippo pathway in regenerative medicine. Our review provides a better understanding of the significance of Hippo pathway in the journey of neuronal system from development to diseases as a whole.