Endogenous Neural Stem Cells Research Articles

Induction of Endogenous Neural Stem Cells By Extracorporeal Shock Waves After Spinal Cord Injury.

Animal experimental study OBJECTIVES.: The purpose of this study is to investigate the effects of extracorporeal shock waves (ESWs) on endogenous neural stem cells (NSCs) proliferation after spinal cord injury (SCI). Exogenous stem cell transplantation for SCI still has many limitations to be addressed such as ideal cell sources, timing of transplantation, and fate of the transplanted cells. Moreover, the efficacy is another issue owing to a peculiar pathologic condition in the chronic phase of SCI. Contusive SCI was made using 24 Sprague-Dawley rats, and ESWs were applied at post-injury 4 weeks in rats. Proliferation and differentiation of endogenous NSCs (DCX, Sox-2) and axonal sprouting (GAP-43 and MAP-2) were observed at 6 weeks after application of ESWs. Differentiation of the activated neural stem cells was also investigated by coexpression of neuronal/glial cell markers (GFAP, Neu N, and CC-1). Immunofluorescence staining and western blotting were performed for quantitative analysis, and these results were compared with those in the control group. For clinical assessment, the BBB locomotor rating scale was performed. More proliferation of endogenous neural stem cells was noted in the experimental groups, and these activated cells were mainly founded in the ependymal layer of the central canal and the injured posterior horn. Differentiation into neuronal and glial cells was also noted in a limited number of cells. With respect to axonal regeneration, GAP-43 and MAP-2 expressions in the experimental groups were also significantly higher than those in the control group. During 6 weeks' clinical observation following ESWs application, functional improvement of the hindlimb was observed without clinical deterioration by trials. Collectively, these findings indicate that ESWs on the chronic phase of SCI induce activation of endogenous NSCs and consequent functional improvement. N/A.

Abstract 60: Sequential Combined Treatment of Pifithrin-a and (+)-phenserine Enhances Neurogenesis and Functional Recovery After Stroke

Background and Purpose: Due to the limitation in treatment window of the rtPA (recombinant tissue plasminogen activator), the development of delayed treatment for stroke is needed. Utilizing a specific p53 inhibitor (PFT-a), our group has previously reported enhanced proliferation and survival of endogenous progenitor cells in-vivo, leading to enhanced functional recovery in stroke animals days and weeks after stroke onset. Recently, a role for amyloid-ß protein precursor (APP) has been implicated in synapse formation, neural plasticity, and the differentiation of neural stem cells. In this study, we examined the efficacy of delayed post-stroke treatment of sequentially combined PFT-a (post-stroke day 5-12) and an amyloid precursor protein inhibitor, (+)-phenserine (post stroke day 13-27) on functional recovery after stroke and the response of endogenous neural progenitor cells in SVZ and SGZ in stroke animals. Methods: We utilized a genetically inducible NSC-specific reporter mouse line (nestin-CreERT2-R26R-YFP) to label and track neural stem cell proliferation, survival, and differentiation in ischemic brain. We evaluated functional recovery at 4 weeks after stroke using locomotion analysis, novel object recognition and Barnes maze tests for cognitive function. Results: Our results show that delayed and combined treatment with PFT-a and (+)-phenserine resulted in increased proliferation and differentiation of YFP positive neuronal stem cells in post-stroke mice compared to vehicle treated stroke mice. In addition, the combined treatment cohort showed improved functional recovery in both locomotor (open field) and cognitive functions (NOR and Barnes maze) starting at 2 weeks post stroke and sustained up to 4 weeks after stroke. Conclusions: Our data suggest that sequential combination treatment strategy that enhances proliferation and neuronal differentiation of endogenous neural stem cells can work synergistically and improve the functional recovery after stroke through increased neurogenesis. This may provide a prolonged treatment window for improving functional recovery after stroke.

The Proliferation Capacity of Cultured Neural Stem Cells Promoted by CSF Collected from SAH Patients Correlates to Clinical Outcome

Neurogenesis from endogenous neural stem cells (NSCs) might contribute to functional recovery after stroke based on animal studies; however, the relationship between neurogenesis and post-stroke outcome has rarely been demonstrated in humans. We prospectively collected cerebrospinal fluid (CSF) from 36 patients with subarachnoid hemorrhage (SAH). The CSF was added to the culture medium of the rat NSCs to test the effects on proliferation (proliferation index [PI], percentage of Ki-67 immunoreactive cells). We correlated the PI with functional outcome based on the modified Rankin Scale at 3 months post-SAH. Treatment with the CSF samples collected from SAH patients showed a higher PI compared with those collected from patients with normal pressure hydrocephalus and untreated controls (20.3 ± 8.8 vs. 8.2 ± 5.1 and 7.8 ± 3.0, P < 0.001), indicating proliferation-promoting factors in CSF after SAH. The PI was positively correlated with SAH volume (p = 0.025). For patients with lower SAH volume, patients with favorable outcome had a higher PI than those with poor outcome (20.8 ± 6.9 vs. 14.6 ± 4.3, p = 0.047). Using multivariable logistic regression analysis, the PI was a positive determinant for favorable outcome (odds ratio, 1.17; 95% confidence interval, 1.00 to 1.36) that more proliferation-promoting factors in CSF was associated with better functional outcome in SAH patients.

Bridging the gap with functional collagen scaffolds: tuning endogenous neural stem cells for severe spinal cord injury repair.

Severe spinal cord injury (SCI) induces massive proliferation of spinal cord neural stem cells (NSCs), which are considered a promising cell source for therapeutic neural repair. However, most injury-activated spinal cord NSCs differentiate into astrocytes, rather than neurons, in the lesion site as a result of the injury-derived microenvironment. In this mini-review, we introduce the concept of tuning injury-activated endogenous NSCs by implantation of functionalized collagen scaffolds for severe SCI repair. The current state of in situ modulation of migration, scar formation, neuronal differentiation, and functional integration of injury-activated NSCs and their progeny by implantation of elaborately modified collagen scaffolds is demonstrated. Moreover, challenges and perspectives for utilizing injury-activated NSCs for regenerative repair of severe SCI are also discussed.

The Potential of Stem Cells in Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rate after TBI, treatment is lacking for brain functional recovery and structural repair in clinic. Recent studies have suggested that the mature brain harbors neural stem cells which have regenerative capacity following brain insults. Much progress has been made in preclinical TBI model studies in understanding the behaviors, functions, and regulatory mechanisms of neural stem cells in the injured brain. Different strategies targeting these cell population have been assessed in TBI models. In parallel, cell transplantation strategy using a wide range of stem cells has been explored for TBI treatment in pre-clinical studies and some in clinical trials. This review summarized strategies which have been explored to enhance endogenous neural stem cell-mediated regeneration and recent development in cell transplantation studies for post-TBI brain repair. Thus far, neural regeneration through neural stem cells either by modulating endogenous neural stem cells or by stem cell transplantation has attracted much attention. It is highly speculated that targeting neural stem cells could be a potential strategy to repair and regenerate the injured brain. Neuroprotection and neuroregeneration are major aspects for TBI therapeutic development. With technique advancement, it is hoped that stem cell-based therapy targeting neuroregeneration will be able to translate to clinic in not so far future.

Ginkgolide B promotes the proliferation and differentiation of neural stem cells following cerebral ischemia/reperfusion injury, both in vivo and in vitro.

Neural stem cells have great potential for the development of novel therapies for nervous system diseases. However, the proliferation of endogenous neural stem cells following brain ischemia is insufficient for central nervous system self-repair. Ginkgolide B has a robust neuroprotective effect. In this study, we investigated the cell and molecular mechanisms underlying the neuroprotective effect of ginkgolide B on focal cerebral ischemia/reperfusion injury in vitro and in vivo. Neural stem cells were treated with 20, 40 and 60 mg/L ginkgolide B in vitro. Immunofluorescence staining was used to assess cellular expression of neuron-specific enolase, glial fibrillary acid protein and suppressor of cytokine signaling 2. After treatment with 40 and 60 mg/L ginkgolide B, cells were large, with long processes. Moreover, the proportions of neuron-specific enolase-, glial fibrillary acid protein- and suppressor of cytokine signaling 2-positive cells increased. A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion. Six hours after ischemia, ginkgolide B (20 mg/kg) was intraperitoneally injected, once a day. Zea Longa's method was used to assess neurological function. Immunohistochemistry was performed to evaluate the proportion of nestin-, neuron-specific enolase- and glial fibrillary acid protein-positive cells. Real-time quantitative polymerase chain reaction was used to measure mRNA expression of brain-derived neurotrophic factor and epidermal growth factor. Western blot assay was used to analyze the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2. Ginkgolide B decreased the neurological deficit score, increased the proportion of nestin-, neuron-specific enolase- and glial fibrillary acid protein-positive cells, increased the mRNA expression of brain-derived neurotrophic factor and epidermal growth factor, and increased the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2 in the ischemic penumbra. Together, the in vivo and in vitro findings suggest that ginkgolide B improves neurological function by promoting the proliferation and differentiation of neural stem cells in rats with cerebral ischemia/reperfusion injury.

Cetuximab and Taxol co-modified collagen scaffolds show combination effects for the repair of acute spinal cord injury.

Injury-activated endogenous neural stem cells (NSCs) in the spinal cord have promising therapeutic applications for rebuilding the neuronal relays after spinal cord injury (SCI) because of their lack of immune-rejection following exogenous cell transplantation. However, these NSCs rarely differentiate into neurons and the damaged axonal regenerative ability is drastically reduced due to the adverse SCI microenvironment. Cetuximab, an EGFR signaling antagonist, has demonstrated the ability of promoting NSC differentiation into neurons. Taxol, in addition to stabilizing microtubules, has shown potential for enhancing axonal regeneration and reducing scar formation after SCI. In this study, we further verified the combined therapeutic effects of Cetuximab and Taxol on inhibition of scar deposition and promotion of neuronal differentiation, axonal outgrowth and functional recovery in a rat severe SCI model. A linear orderly collagen scaffold modified with Cetuximab and Taxol was grafted into the SCI site after the complete removal of 4 mm of spinal tissue. The results showed that the combined functional scaffold implantation significantly increased neural regeneration to reconnect the neural network. Moreover, scaffold transplantation decreases the deposition of varied scar-related inhibitors within the lesion center, further reflecting the need for a combination dedicated to increasing motor function following SCI. Collagen scaffold based-combined therapy provides a potential strategy for improving functional restoration of the injured spinal cord.

Stem Cell Therapies for Neurodegenerative Diseases.

Stem cell therapies have been proposed as a treatment option for neurodegenerative diseases, but the best stem cell source and therapeutic efficacy for neuroregeneration remain uncertain. Embryonic stem cells (ESCs) and neural stem cells (NSCs), which can efficiently generate neural cells, could be good candidates but they pose ethical and practical issues. Not only difficult to find the good source of those cells but also they alway pose immunorejection problem since they may not be an autologous cells. Even if we overcome the immunorejection problem, it has also been reported that transplantation of ESCs develop teratoma. Although adult stem cells are more accessible, they have a limited developmental potential. We developed technologies to increase potency of mesenchymal stem cells, which allow them to develop into neural cells, by over expression of the ESC gene, nanog. We also developed a small molecule compound, which significantly increases endogenous NSCs by peripheral administration, eliminating even the necessity of stem cell injection to the brain. These novel technologies may offer neuroregenerative therapies for Alzheimers disease (AD). However, we found that AD pathological condition prevent neurogenesis from NSCs. This chapter discusses how to overcome the problem associated stem cell therapy under AD pathology and introduces exosome as a tool to improve the modification of adult stem cells. These new technologies may open a door for the new era for AD therapy.

Spatial and Sex-Dependent Responses of Adult Endogenous Neural Stem Cells to Alcohol Consumption.

SummaryChronic alcohol abuse results in alcohol-related neurodegeneration, and critical gaps in our knowledge hinder therapeutic development. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that contribute to brain maintenance and recovery. While it is known that alcohol alters NSCs, little is known about how NSC response to alcohol is related to sex, brain region, and stage of differentiation. Understanding these relationships will aid in therapeutic development. Here, we used an inducible transgenic mouse model to track the stages of differentiation of adult endogenous NSCs and observed distinct NSC behaviors in three brain regions (subventricular zone, subgranular zone, and tanycyte layer) after long-term alcohol consumption. Particularly, chronic alcohol consumption profoundly affected the survival of NSCs in the subventricular zone and altered NSC differentiation in all three regions. Significant differences between male and female mice were further discovered.

Pediatric brain repair from endogenous neural stem cells of the subventricular zone

There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the germinal zones of the immature brain. Studies using animal models of pediatric brain injuries have provided a clearer understanding of the responses of these progenitors to injury. In this review, we have compared and contrasted the responses of the endogenous neural stem cells and progenitors of the subventricular zone in animal models of neonatal cerebral hypoxia-ischemia, neonatal stroke, congenital cardiac disease, and pediatric traumatic brain injury. We have reviewed the dynamic shifts that occur within this germinal zone with injury as well as changes in known signaling molecules that affect these progenitors. Importantly, we have summarized data on the extent to which cell replacement occurs in response to each of these injuries, opportunities available, and obstacles that will need to be overcome to improve neurological outcomes in survivors.

Erythropoietin signaling increases neurogenesis and oligodendrogenesis of endogenous neural stem cells following spinal cord injury both invivo and invitro.

Erythropoietin (Epo) promotes functional recovery following spinal cord injury (SCI); however, the exact underlying mechanisms are yet to be determined. Although endogenous neural stem cells (NSCs) in the adult spinal cord are a therapeutic target in SCI models, the effect of Epo on this NSC population remains unknown. The present study investigated the effects of Epo on endogenous NSCs in the adult spinal cord both in vitro and in vivo. For the in vivo analyses, normal rats (Normal) and SCI contusion model rats (SCI) received either recombinant human Epo or saline treatment for 7 days (5,000 U/kg), and spinal cords were subsequently analyzed at 2, 8, and 14 days. For in vitro analyses, NSCs harvested from adult rat spinal cords were exposed to Epo (10 U/ml). A significant increase in β-tubulin+ new neurons (P<0.01) was observed at all three time points and O4+ new oligodendrocytes (P<0.05) at days 8 and 14 in the SCI+Epo group compared with the SCI+Saline group. This was concomitant with a prolonged activation of Epo signaling; however, no effect on NSCs proliferation was observed. Similar results were also obtained in vitro. Motor functional recovery was also noted at days 8 and 14 only in the Epo-treated SCI rats. Although the expression of Epo and EpoR significantly increased in Normal+Epo rats compared with Normal+Saline rats (P<0.05), the cell numbers and phenotype were comparable between the two groups. To the best of the author's knowledge, this is the first study to demonstrate that Epo signaling promotes both neurogenesis and oligodendrogenesis following SCI and that these may represent the underlying mechanisms for the functional recovery and therapeutic effects of Epo following SCI.

Baicalin and ginsenoside Rb1 promote the proliferation and differentiation of neural stem cells in Alzheimer’s disease model rats

BackgroundThis study aimed to explore the effects of ginsenoside Rb1 and baicalin on the proliferation and differentiation of neural stem cells (NSC) in Alzheimer’s disease model rats. MethodThe healthy Sprague Dawley male rats were randomly divided into 4 groups: control group, model group, ginsenoside Rb1 group and baicalin group. Besides, the animal model of dementia was induced by the injection of Aβ1-40. 2 weeks later, the rats in the baicalin and ginsenoside Rb1 groups were injected with baicalin and ginsenoside Rb1, respectively. The contents, expression sites of Nestin, GFAP and NSE and the percentage of viable cells were detected by immunohistochemistry. In addition, the expression levels of Nestin, GFAP and NSE in hippocampus of rats were detected by western-blot and metrology analysis was performed using quantity. ResultsInjection of Aβ1-40 significantly reduced the number of neuronal cells (p < .05). In addition, compared with the control group, the percentages of positive cells of NSCs, astrocytes and neuronal were increased. Besides, compared with the model group, the percentage of positive neural cells was improved by ginsenoside Rb1 (p < .05), and the percentages of astrocytes and neuronal were increased by ginsenoside Rb1 and baicalin (p < .05). Moreover, the expressions of Nestin and NSE were enhanced by ginsenoside Rb1 and baicalin (p < .05), while the GFAP level was only affected by ginsenoside Rb1 (p < .05) when compared with the model group. ConclusionGinsenoside Rb1 and baicalin might promote the proliferation and differentiation of endogenous NSCs in AD rat model.

Endogenous neural stem cells promotes Notch-1 expression after spinal cord injury in rats

Objective To explore the expressions and changes of endogenous neural stem cells (ENSCs) and Notch-1 after acute spinal cord injury in adult rats, and to explore its role in the nerve regeneration process. Methods The 30 Sprague Dawley (SD) female rats (3-6 months) (300-350 g) were divided into control groups (n=5) and experimental group (n=25) by digital random method. The control group only accepted lamina decompression, and the experimental group was the spinal cord injury group. Five rats were drawn when at 1 d, 3 d, 1 w, 2 w, and 4 w, then behavior, histology, immunohistochemistry and immunofluorescence method were used to detect the proliferation and expression of endogenous neural stem cells and Notch-1 protein. Results Behavioral observation showed the experimental group rats were disfunction. Histological observation showed nerve fiber structure turbulence, edema and denaturation in the experimental group. Immunohistochemistry staining showed the Notch-1 expression every experimental group. Notch-1 positive cell peaked at 3 days. Immunofluorescence test showed, in the experimental group damage to segment the area surrounding the BrdU positive staining cells was significantly higher than the control group. Using three-dimensional quantitative study method detected in 1w after spinal cord injury was the number of newborn cells mitosis, most about was about 75 times in the control group. Linear regression method was used to analyze the different time points after BrdU and Notch-1 protein expression positive area, the area of the results found that both into linear correlation. Conclusions The new born neurons after spinal cord injury in rats Notch-1 expression has a certain relevance. In addition, the expression of signal protein Notch-1, might be associated with early proliferation of ENSCs in rats. Key words: Spinal cord injuries; Receptor, Notch1; Stem cells; Nervous system/CY; Nerve regeneration

Prickle1 as positive regulator of oligodendrocyte differentiation

Spontaneous neural repair from endogenous neural stem cells’ (NSCs) niches occurs in response to central nervous system (CNS) injuries to only a limited extent. Uncovering the mechanisms that control neural repair and can be further manipulated to promote NSCs toward oligodendrocyte progenitors cells (OPCs) and myelinating oligodendrocytes is a major objective. In the current study, we describe high-throughput transcriptional changes in adult mouse subventricular zone (SVZ)-NSCs during differentiation in vitro. In order to identify myelin-specific transcriptional regulators among large transcriptional changes associated with differentiation, we have focused on transcripts encoding transcription factors and regulators showing expression profile that is highly correlated with expression of myelin-encoding genes. We have revealed previously undescribed effect of Prickle1 and Nfe2l3 transcriptional regulators that are positively correlated with expression of myelin basic protein (MBP). Using Prickle1 and Nfe2l3 silencing and immunocytochemistry approaches, we demonstrated that silencing of Prickle1 dramatically decreases differentiation to NG2+OPCs while Nfe2l3 moderately decreases as compared with control siRNA. Moreover, silencing of Prickle1 also decreases maturation of OPCs to MBP+ oligodendrocytes (OLs). Accordingly, overexpression of Prickle1 increases the differentiation of NSCs to CNPase+ pre-myelinating and myelinating MBP+ OLs. In particular, the necessity of Prickle1 for oligodendrocyte differentiation is demonstrated in purified OPCs cultures. Our findings demonstrate the role of Prickle1 in positive regulation of differentiation and maturation of oligodendrocytes suggesting that targeting Prickle1 in CNS injuries and particularly in demyelinating disease could promote generation of myelinating oligodendrocytes from endogenous niches to replenish damaged oligodendrocytes.

Effects of sphingosine-1-phosphate receptor 1 alteration on proliferation of neural stem cells in hippocampus after traumatic brain injury

Objective To investigate the effects of sphingosine-1- phosphate receptor 1 (S1PR1) changes on the proliferation of endogenous neural stem cells (NSCs) in hippocampus after traumatic brain injury (TBI). Methods Rat TBI models were constructed by the means of controlled cortical injury. A total of 72 rats were included and randomly divided into four groups: sham, TBI, TBI+ SEW (TBI+ S1PR1 agonist SEW2871 intervention) and TBI+ VPC group (TBI+ S1PR1 antagonist VPC23019 intervention), with 18 rats per group. The TBI model was induced by a control cortical injury device. The injured rats in TBI+ SEW group and TBI+ VPC group were respectively administrated with S1PR1 agonist SEW2871 and antagonist VPC23019 at scheduled time points after TBI. Hippocampal S1PR1 expression was detected by Western-blotting and the proliferation of NSCs was assessed by double-labeled immunofluorescence staining at days 7, 14 and 21 after injury. Results At days 7, 14 and 21 after TBI, the hippocampal S1PR1 levels and NSCs proliferation amounts in sham, TBI, TBI+ SEW and TBI+ VPC groups were evidently different (P<0.05). In particular, the outstanding changes among the four groups above occurred at 7 d after injury were as following: S1PR1 expression in TBI group significantly increased by 1.56 times compared with that in sham group, and it was respectively up-regulated by 66.67% in TBI+ SEW group and down-regulated by 20.29% in TBI+ VPC group (P<0.05). The number of NSCs proliferation in TBI group was 2.08 times more than that in sham group, and it increased by 36.75% in TBI+ SEW group and reduced by 18.77% in TBI+ VPC group(P<0.05). Conclusion The expression of S1PR1 is closely associated with the proliferation of NSCs in hippocampus after TBI, indicating that S1PR1 activation may be an effective strategy to improve the post-traumatic neurogenesis. Key words: Brain injuries; Neural stem cells; Nerve regeneration; Sphingosine-1-phosphate receptor 1

HMGB1/Advanced Glycation End Products (RAGE) does not aggravate inflammation but promote endogenous neural stem cells differentiation in spinal cord injury

Receptor for advanced glycation end products (RAGE) signaling is involved in a series of cell functions after spinal cord injury (SCI). Our study aimed to elucidate the effects of RAGE signaling on the neuronal recovery after SCI. In vivo, rats were subjected to SCI with or without anti-RAGE antibodies micro-injected into the lesion epicenter. We detected Nestin/RAGE, SOX-2/RAGE and Nestin/MAP-2 after SCI by Western blot or immunofluorescence (IF). We found that neural stem cells (NSCs) co-expressed with RAGE were significantly activated after SCI, while stem cell markers Nestin and SOX-2 were reduced by RAGE blockade. We found that RAGE inhibition reduced nestin-positive NSCs expressing MAP-2, a mature neuron marker. RAGE blockade does not improve neurobehavior Basso, Beattie and Bresnahan (BBB) scores; however, it damaged survival of ventral neurons via Nissl staining. Through in vitro study, we found that recombinant HMGB1 administration does not lead to increased cytokines of TNF-α and IL-1β, while anti-RAGE treatment reduced cytokines of TNF-α and IL-1β induced by LPS via ELISA. Meanwhile, HMGB1 increased MAP-2 expression, which was blocked after anti-RAGE treatment. Hence, HMGB1/RAGE does not exacerbate neuronal inflammation but plays a role in promoting NSCs differentiating into mature neurons in the pathological process of SCI.

Manipulation of neural progenitor fate through the oxygen sensing pathway.

Neural progenitor cells hold significant promise in a variety of clinical settings. While both the brain and spinal cord harbor endogenous neural progenitor or stem cells, they typically are not capable of repopulating neural populations in case of injury or degenerative disease. In vitro systems for the culture of neural progenitors has come a long ways due to advances in the method development. Recently, many groups have shown that manipulation of the oxygen-sensing pathway leading to activation of hypoxia inducible factors (HIFs) that can influence the proliferation, differentiation or maturation of neural progenitors. Moreover, different oxygen concentrations appear to affect lineage specification of neural progenitors upon their differentiation in vitro. Here we summarize some of these studies in an attempt to direct effort towards implementation of best methods to advance the use of neural progenitors from basic development towards clinical application.

Osthole promotes endogenous neural stem cell proliferation and improved neurological function through Notch signaling pathway in mice acute mechanical brain injury

Mechanical brain injury (MBI) is a common neurotrosis disorder of the central nervous system (CNS), which has a higher mortality and disability. In the case of MBI, neurons death leads to loss of nerve function. To date, there was no satisfactory way to restore neural deficits caused by MBI. Endogenous neural stem cells (NSCs) can proliferate, differentiate and migrate to the lesions after brain injury, to replace and repair the damaged neural cells in the subventricular zone (SVZ), hippocampus and the regions of brain injury. In the present study, we first prepared a mouse model of cortical stab wound brain injury. Using the immunohistochemical and hematoxylin-eosin (H&E) staining method, we demonstrated that osthole (Ost), a natural coumarin derivative, was capable of promoting the proliferation of endogenous NSCs and improving neuronal restoration. Then, using the Morris water maze (MWM) test, we revealed that Ost significantly improved the learning and memory function in the MBI mice, increased the number of neurons in the regions of brain injury, hippocampus DG and CA3 regions. Additionally, we found that Ost up-regulated the expression of self-renewal genes Notch 1 and Hes 1. However, when Notch activity was blocked by the γ-secretase inhibitor DAPT, the expression of Notch 1 and Hes 1 mRNA was down-regulated, augmentation of NICD and Hes 1 protein was ameliorated, the proliferation-inducing effect of Ost was abolished. These results suggested that the effects of Ost were at least in part mediated by activation of Notch signaling pathway. Our findings support that Ost is a potential drug for treating MBI due to its neuronal restoration.

Monocyte depletion early after stroke promotes neurogenesis from endogenous neural stem cells in adult brain

Ischemic stroke, caused by middle cerebral artery occlusion, leads to long-lasting formation of new striatal neurons from neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) of adult rodents. Concomitantly with this neurogenic response, SVZ exhibits activation of resident microglia and infiltrating monocytes. Here we show that depletion of circulating monocytes, using the anti-CCR2 antibody MC-21 during the first week after stroke, enhances striatal neurogenesis at one week post-insult, most likely by increasing short-term survival of the newly formed neuroblasts in the SVZ and adjacent striatum. Blocking monocyte recruitment did not alter the volume of the ischemic lesion but gave rise to reduced astrocyte activation in SVZ and adjacent striatum, which could contribute to the improved neuroblast survival. A similar decrease of astrocyte activation was found in and around human induced pluripotent stem cell (iPSC)-derived NSPCs transplanted into striatum at one week after stroke in monocyte-depleted mice. However, there was no effect on neurogenesis in the graft as determined 8weeks after implantation. Our findings demonstrate, for the first time, that a specific cellular component of the early inflammatory reaction in SVZ and adjacent striatum following stroke, i.e., infiltrating monocytes, compromises the short-term neurogenic response neurogenesis from endogenous NSPCs.

Transcriptome profiling of the subventricular zone and dentate gyrus in an animal model of Parkinson's disease.

Adult neurogenesis in the subventricular zone (SVZ), as well as in the subgranular zone contributes to brain maintenance and regeneration. In the adult brain, dopamine (DA) can regulate the endogenous neural stem cells within these two regions, while a DA deficit may affect neurogenesis. Notably, the factors that regulate in vivo neurogenesis in these subregions have not yet been fully characterized, particularly following DA depletion. In thi study, we performed RNA sequencing to investigate transcriptomic changes in the SVZ and dentate gyrus (DG) of mice in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This analysis identified differentially expressed genes which were involved in the regulation of transcription, immune response, extracellular region, cell junction and myelination. These genes partially displayed different temporal profiles of expression, some of which may participate in the metabolic switch related to neurogenesis. Additionally, the mitogen-activated protein kinase (MAPK) signaling pathway was shown to be been positively regulated in the SVZ, while it was negatively affected in the DG following MPTP administration. Overall, our findings indicate that exposure to MPTP may exert different effects on transcriptome profiling between the SVZ and DG.