Adult Neural Progenitor Cells Research Articles

SMAD7 deficiency stimulates Müller progenitor cell proliferation during the development of the mammalian retina.

The transforming growth factor-β (TGF-β) pathway contributes to maintain the quiescence of adult neural stem and progenitor cells in the brain. In the retina, Müller cells are discussed to represent a glial cell population with progenitor-like characteristics. Here, we aimed to investigate if elevated TGF-β signaling modulates the proliferation of Müller cells during retinal development. We generated mutant mice with a systemic, heterozygous up-regulation of TGF-β signaling by deleting its inhibitor SMAD7. We investigated apoptosis, proliferation, and differentiation of Müller cells in the developing retina. We show that a heterozygous deletion of SMAD7 results in an increased proliferation of Müller cell progenitors in the central retina at postnatal day 4, the time window when Müller cells differentiate in the mouse retina. This in turn results in a thickened retina and inner nuclear layer and a higher number of differentiated Müller cells in the more developed retina. Müller cells in mutant mice contain higher amounts of nestin than those of control animals which indicates that the increase in TGF-β signaling activity during retinal development contribute to maintain some progenitor-like characteristics in Müller cells even after their differentiation period. We conclude that TGF-β signaling influences Müller cell proliferation and differentiation during retinal development.

Magnesium Elevation Promotes Neuronal Differentiation While Suppressing Glial Differentiation of Primary Cultured Adult Mouse Neural Progenitor Cells through ERK/CREB Activation.

This study aimed to explore the influence of magnesium elevation on fate determination of adult neural progenitor cells (aNPCs) and the underlying mechanism in vitro. Adult neurogenesis, which is the generation of functional neurons from neural precursors, occurs throughout life in restricted anatomical regions in mammals. Magnesium is the fourth most abundant ion in mammals, and its elevation in the brain has been shown to enhance memory and synaptic plasticity in vivo. However, the effects of magnesium on fate determination of aNPCs, which are vital processes in neurogenesis, remain unknown. NPCs isolated from the dentate gyrus of adult C57/BL6 mice were induced to differentiate in a medium with varying magnesium concentrations (0.6, 0.8, and 1.0 mM) and extracellular signal-regulated kinase (ERK) inhibitor PD0325901. The proportion of cells that differentiated into neurons and glial cells was evaluated using immunofluorescence. Quantitative real-time polymerase chain reaction and Western blot methods were used to determine the expression of β-III tubulin (Tuj1) and glial fibrillary acidic protein (GFAP). The activation of ERK and cAMP response element-binding protein (CREB) was examined by Western blot to reveal the underlying mechanism. Magnesium elevation increased the proportion of Tju1-positive cells and decreased the proportion of GFAP-positive cells. Also, the expression of Tuj1 was upregulated, whereas the expression of GFAP was downregulated. Moreover, magnesium elevation enhanced the activation of both ERK and CREB. Treatment with PD0325901 reversed these effects in a dose-dependent manner. Magnesium elevation promoted neural differentiation while suppressing glial cell differentiation, possibly via ERK-induced CREB activation.

Abstract WMP48: Cerebral Endothelial Derived Exosomes Abolish Cognitive Impairment Induced by Ablation of Dicer in Adult Neural Progenitor Cells

Introduction: Dicer processes precursor miRNAs into mature miRNAs. We have demonstrated that conditional knockout of Dicer (Dicer/Cko) in adult neural progenitor cells (NPCs) impairs neurogenesis and cognitive function. The present study tested the hypothesis that cerebral endothelial-derived exosomes carrying mature miRNAs promote neurogenesis and improve cognitive function by communication with NPCs in Dicer/Cko mice. Methods and Results: Exosomes harvested from cultured cerebral endothelial cells (CEC-Ex, 1x10 9 exosomes) were intranasally administered twice a week for two consecutive weeks into mice (n=10) with conditional ablation of Dicer (Dicer/Cko) in NPCs ( Ascl1- CreER :Dicer flox/flox ). Dicer/Cko mice treated with saline (n=12) were used as control. Cognitive tests were performed, including Morris Water Maze (MWM) for hippocampal related learning and memory, odor-based novelty recognition for olfactory memory, and social interaction for memory of interactions with novel conspecifics. Compared to wild-type mice, Dicer/Cko mice treated with saline exhibited substantial cognitive impairment. The CEC-Ex treatment diminished cognitive deficits and these mice exhibited an increase of 40% more time spent in the correct quadrant (p<0.05) of the MWM, and increased time exploring new odor objects (71±9% vs 41 ±10% saline, p<0.05) and increased time in contact with a strange mouse during the sociability test. Using a Cre/flox reporter approach, we found that the exosomes carrying Cre mRNA entered NPCs in the subventricular zone (SVZ) and dentate gyrus (DG). The CEC-Ex treatment significantly (p<0.05) increased BrdU + NPCs (20 ± 1% vs 14 ± 2%, SVZ, 16±1% vs 12±3%, DG ) and DCX+ neuroblasts (27 ± 2% vs 22 ± 3%, SVZ, 33 ± 2% vs 25 ± 3%, DG), and reduced apoptotic cells by more than 50% in these two areas. RT-PCR analysis showed that Dicer/Cko mice exhibited substantial reduction of mature miRNAs that regulate neurogenesis including miR-124, -146a and -17-92 cluster in NPCs, whereas the CEC-Ex treatment increased these mature miRNAs in Dicer/Cko NPCs. Conclusion: The CEC-Ex can reverse impaired neurogenesis and cognitive function induced by ablation of Dicer, which is likely attributed to the delivery of mature miRNAs into NPCs by CEC-Ex.

Abstract 141: The Microrna 17-92 Cluster in Neural Progenitor Cells is Required for Stroke-induced Neurogenesis and Gliogenesis

Background: Molecular mechanisms underlying stroke-induced neurogenesis have not been fully investigated. The microRNA 17-92 cluster (miR17-92) regulates proliferation and differentiation of adult neural progenitor cells (NPCs). The present study investigated whether the miR17-92 cluster in NPCs is required for stroke-induced neurogenesis. Methods and Results: Mice with inducible and conditional knockdown of the miR17-92 cluster in nestin lineage NPCs (nestin-CreER T2 /miR17-92 -/- , 17-92-cKO, n=9) and wild-type litters (WT, n=9) were treated by tamoxifen. Administration of tamoxifen resulted in more than 60% reduction of individual members of the miR-17-92 cluster (miR-17: 1.0 vs 0.4; miR-19a: 1.0 vs 0.3; miR-19b: 1.0 vs 0.2; miR-20a: 1.0 vs 0.4; miR-92a: 1.0 vs 0.4 fold in WT, p<0.05) in NPCs localized to the subventricular zone (SVZ). Two days after termination of tamoxifen treatment, these mice were subjected to permanent right middle cerebral artery occlusion (MCAO) and sacrificed 28 days post-MCAo. Compared to WT mice, 17-92-cKO mice exhibited significant (p<0.05) reduction of proliferation of NPCs measured by the number of Ki67 + cells (226±43 vs 471±100 cells/mm 2 ) and the number of DCX + neuroblasts (11±2% vs 24±4% ) in the ischemic SVZ. Cultured NPCs harvested from ischemic cKO mice showed significant (p<0.05) reduction of BrdU + cells (37±2% vs 61±4% WT , n=3/group), Tuj1 + neuroblasts (5±0.2% vs 9±0.4% ), GFAP + cells (33±3% vs 53±2% ), and NG2 + oligodendrocyte progenitor cells (OPCs, 3±0.1% vs 5±0.5%). These in vivo and in vitro data indicate that reduction of the miR17-92 cluster suppresses stroke-induced neurogenesis and gliogenesis. Western blot analysis showed that miR17-92 cKO significantly (p<0.05) increased and reduced a cytoskeleton-associated protein, Enigma homolog1 (ENH1, 1.6 vs 1.0 fold), and its down-stream transcription factor, inhibitor of differentiation1 (ID1, 1.0 vs 0.6 fold), respectively. ENH1 is a putative target of the miR17-92 cluster. Conclusion: Our data indicate that the miR17-92 cluster in adult nestin lineage NPCs is required for stroke-induced neurongenesis and gliogenesis, and that the miR17-92 cluster possibly targets ENH1/ID1 signaling.

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Adult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

Novel insights into the role of NF-κB p50 in astrocyte-mediated fate specification of adult neural progenitor cells.

Within the CNS nuclear factor-kappa B (NF-κB) transcription factors are involved in a wide range of functions both in homeostasis and in pathology. Over the years, our and other groups produced a vast array of information on the complex involvement of NF-κB proteins in different aspects of postnatal neurogenesis. In particular, several extracellular signals and membrane receptors have been identified as being able to affect neural progenitor cells (NPC) and their progeny via NF-κB activation. A crucial role in the regulation of neuronal fate specification in adult hippocampal NPC is played by the NF-κB p50 subunit. NF-κB p50KO mice display a remarkable reduction in adult hippocampal neurogenesis which correlates with a selective defect in hippocampal-dependent short-term memory. Moreover absence of NF-κB p50 can profoundly affect the in vitro proneurogenic response of adult hippocampal NPC (ahNPC) to several endogenous signals and drugs. Herein we briefly review the current knowledge on the pivotal role of NF-κB p50 in the regulation of adult hippocampal neurogenesis. In addition we discuss more recent data that further extend the relevance of NF-κB p50 to novel astroglia-derived signals which can influence neuronal specification of ahNPC and to astrocyte-NPC cross-talk.

Distinct roles of neuroepithelial-like and radial glia-like progenitor cells in cerebellar regeneration

Zebrafish can regenerate after brain injury, and the regenerative process is driven by resident stem cells. Stem cells are heterogeneous in the vertebrate brain, but the significance of having heterogeneous stem cells in regeneration is not understood. Limited availability of specific stem cells might impair the regeneration of particular cell lineages. We studied regeneration of the adult zebrafish cerebellum, which contains two major stem and progenitor cell types: ventricular zone and neuroepithelial cells. Using conditional lineage tracing we demonstrate that cerebellar regeneration depends on the availability of specific stem cells. Radial glia-like cells are thought to be the predominant stem cell type in homeostasis and after injury. However, we find that radial glia-like cells play a minor role in adult cerebellar neurogenesis and in recovery after injury. Instead, we find that neuroepithelial cells are the predominant stem cell type supporting cerebellar regeneration after injury. Zebrafish are able to regenerate many, but not all, cell types in the cerebellum, which emphasizes the need to understand the contribution of different adult neural stem and progenitor cell subtypes in the vertebrate central nervous system.

Enhancement of Striatal Dopaminergic Function Following Autologous Neural Cell Ecosystems (ANCE) Transplantation in a Non-Human Primate Model of Parkinson’s Disease

Objective: Previous evidence was provided that parkinsonian monkeys exhibited significant though incomplete behavioral recovery following a cell therapy consisting of auto-transplantation of adult neural progenitor cells. The aim of the present study was to assess for the first time in this parkinsonian non-human primate model the striatal dopaminergic function, in parallel to further behavioral assessment. In other words, is the behavioral recovery associated to a reversal of dopaminergic function despite the auto-transplanted cells are not dopaminergic. Methods: Striatal dopaminergic function and motor behavior (spontaneous motion activities) were monitored in adult parkinsonian macaques in relation to autologous neural cell ecosystem (ANCE) transplantation. In four MPTP intoxicated macaques, adult progenitor cells derived from cortical biopsies were re-implanted in the same animal after a phase of spontaneous functional recovery. The function of the striatal dopaminergic system was assessed using 18F-DOPA positron tomography imaging and the motor function was quantified. Results: Two parkinsonian animals exhibited severe motor symptoms, which were moderate and transient in two other monkeys. 18F-DOPA striatal uptake decreased by 80% in three animals, consistent with losses of dopaminergic neurons in substantia nigra and reduced striatal density of dopaminergic projections. Six months after autologous transplantation, all animals improved their motor functions. This functional recovery was largely consistent with positron emission tomography results showing some recovery of 18F-DOPA striatal uptake toward baseline value following transplantation. Conclusion: The present data confirm that symptoms are variable across individual parkinsonian monkeys and that autologous neural cell ecosystem transplantation indeed attenuates parkinsonian motor symptoms. Yet the present study provides for the first time evidence in favor of an increase in the striatal dopaminergic activity that correlates with motor recovery in this novel therapeutic approach, although the implanted cells are not dopaminergic.

Cell autonomous and noncell‐autonomous role of NF‐κB p50 in astrocyte‐mediated fate specification of adult neural progenitor cells

In previous work, we demonstrated that NF-κB p50 acts as crucial regulator of adult hippocampal neural progenitor cells (ahNPC). Indeed, NF-κB p50 knockout (KO) mice are characterized by remarkably reduced hippocampal neurogenesis. As a follow up to that work, herein we show that when cultured in vitro, ahNPC from wild type (WT) and p50KO mice are not significantly different in their neurogenic potential. This observation prompted us to investigate cell-autonomous and noncell-autonomous consequences of p50 absence on neuronal fate specification of ahNPC. In particular, we focused our attention on astrocytes, known to provide soluble proneurogenic signals, and investigated the influence of WT and p50KO astrocyte conditioned media (ACM) on WT and p50KO ahNPC differentiation. Interestingly, while WT ACM promoted both neuronal and astroglial differentiations, p50KO ACM only supported astroglial differentiation of WT ahNPC. By using a LC-MS/MS approach, we identified some proteins, which are significantly upregulated in p50KO compared with WT astrocytes. Among them, lipocalin-2 (LCN-2) was recognized as a novel astroglial-derived signal regulating neuronal fate specification of ahNPC. Interestingly, LCN-2 proneurogenic effect was greatly reduced in p50KO NPC, where LCN-2 receptor gene expression appeared downregulated. In addition to that, we demonstrated p50KO NPC unresponsiveness to both neuronal and astroglial fate specification signals from WT and p50KO ACM, and we identified a reduced expression of α2δ1, a thrombospondin-1 receptor, as another phenotypic change occurring in ahNPC in the absence of p50. Altogether, our data suggest that dysregulated NPC-astrocyte communication may contribute to a reduced hippocampal neurogenesis in p50KO mice in vivo. GLIA 2016 GLIA 2017;65:169-181.

P.1.g.037 - New insights on trazodone effect in promoting neuronal differentiation of adult murine hippocampal neural progenitor cells

P.1.g.037 - New insights on trazodone effect in promoting neuronal differentiation of adult murine hippocampal neural progenitor cells

Regulation of adult neural progenitor cell functions by purinergic signaling.

Extracellular purines are signaling molecules in the neurogenic niches of the brain and spinal cord, where they activate cell surface purinoceptors at embryonic neural stem cells (NSCs) and adult neural progenitor cells (NPCs). Although mRNA and protein are expressed at NSCs/NPCs for almost all subtypes of the nucleotide-sensitive P2X/P2Y, and the nucleoside-sensitive adenosine receptors, only a few of those have acquired functional significance. ATP is sequentially degraded by ecto-nucleotidases to ADP, AMP, and adenosine with agonistic properties for distinct receptor-classes. Nucleotides/nucleosides facilitate or inhibit NSC/NPC proliferation, migration and differentiation. The most ubiquitous effect of all agonists (especially of ATP and ADP) appears to be the facilitation of cell proliferation, usually through P2Y1Rs and sometimes through P2X7Rs. However, usually P2X7R activation causes necrosis/apoptosis of NPCs. Differentiation can be initiated by P2Y2R-activation or P2X7R-blockade. A key element in the transduction mechanism of either receptor is the increase of the intracellular free Ca2+ concentration, which may arise due to its release from intracellular storage sites (G protein-coupling; P2Y) or due to its passage through the receptor-channel itself from the extracellular space (ATP-gated ion channel; P2X). Further research is needed to clarify how purinergic signaling controls NSC/NPC fate and how the balance between the quiescent and activated states is established with fine and dynamic regulation. GLIA 2017;65:213-230.

SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation

Evidence has shown that stromal cell-derived factor (SDF-1/CXCL12) plays an important role in maintaining adult neural progenitor cells (NPCs). SDF-1 is also known to enhance recovery by recruiting NPCs to damaged regions and recent studies have revealed that SDF-1α exhibits pleiotropism, thereby differentially affecting NPC subpopulations. In this study, we investigated the role of SDF-1 in in vitro NPC self-renewal, proliferation and differentiation, following treatment with different concentrations of SDF-1 or a CXCR4 antagonist, AMD3100. We observed that AMD3100 inhibited the formation of primary neurospheres. However, SDF-1 and AMD3100 exhibited no effect on proliferation upon inclusion of growth factors in the media. Following growth factor withdrawal, AMD3100 and SDF-1 treatment resulted in differential effects on NPC proliferation. SDF-1, at a concentration of 500ng/ml, resulted in an increase in the relative proportion of oligodendrocytes following growth factor withdrawal-induced differentiation. Using CXCR4 knockout mice, we observed that SDF-1 affected NPC proliferation in the sub-ventricular zone (SVZ). We also investigated the occurrence of differential CXCR4 expression at different stages during lineage progression. These results clearly indicate that signaling interactions between SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation.

Cell type-dependent Erk-Akt pathway crosstalk regulates the proliferation of fetal neural progenitor cells.

Neural progenitor (NP) cells are the multipotent cells that produce neurons and glia in the central nervous system. Compounds regulating their proliferation are key to both understanding brain development and unlocking their potential in regenerative repair. We discuss a chemical screen that unexpectedly identified inhibitors of Erk signaling potently promoting the self-renewing divisions of fetal NP cells. This occurred through crosstalk between Erk and Akt signaling cascades. The crosstalk mechanism is cell type-specific, and is not detected in adult NP cells as well as brain tumor cells. The mechanism was also shown to be independent from the GSK-3 signaling pathway, which has been reported to be a major regulator of NP cell homeostasis and inhibitors to which were also identified in the screen. In vitro Erk inhibition led to the prolonged rapid expansion of fetal NP cells while retaining their multipotency. In vivo inhibitor administration significantly inhibited the neuronal differentiation, and resulted in increased proliferative progenitor cells in the ventricular/subventricular zone (VZ/SVZ) of the embryonic cortex. Our results uncovered a novel regulating pathway for NP cell proliferation in the developing brain. The discovery provides a pharmacological basis for in vitro expansion and in vivo manipulation of NP cells.

Reductions in hypothalamic Gfap expression, glial cells and α-tanycytes in lean and hypermetabolic Gnasxl-deficient mice.

BackgroundNeuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein Gαs, termed XLαs, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated.ResultsRNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive α-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3rd ventricle, while β-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes.ConclusionGnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since α-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0219-1) contains supplementary material, which is available to authorized users.

How Does Transcranial Magnetic Stimulation Influence Glial Cells in the Central Nervous System?

Transcranial magnetic stimulation (TMS) is widely used in the clinic, and while it has a direct effect on neuronal excitability, the beneficial effects experienced by patients are likely to include the indirect activation of other cell types. Research conducted over the past two decades has made it increasingly clear that a population of non-neuronal cells, collectively known as glia, respond to and facilitate neuronal signaling. Each glial cell type has the ability to respond to electrical activity directly or indirectly, making them likely cellular effectors of TMS. TMS has been shown to enhance adult neural stem and progenitor cell (NSPC) proliferation, but the effect on cell survival and differentiation is less certain. Furthermore there is limited information regarding the response of astrocytes and microglia to TMS, and a complete paucity of data relating to the response of oligodendrocyte-lineage cells to this treatment. However, due to the critical and yet multifaceted role of glial cells in the central nervous system (CNS), the influence that TMS has on glial cells is certainly an area that warrants careful examination.

Toxic Immunoglobulin Light Chain Autoantibodies are Associated with a Cluster of Severe Complications in Older Adult Type 2 Diabetes.

To assess neuronal depolarization evoked by autoantibodies in diabetic depression compared to depolarization evoked by autoantibodies in control patients. To determine whether a subset of severe (late-onset) diabetic complications may be mediated in part by toxic immunoglobulin light chains that may increase in diabetic nephropathy. Protein-A eluates from plasma of 21 diabetic depression patients and 37 age-matched controls were tested for depolarization in hippocampal or immature neurons. Subsets of depolarizing or non-depolarizing autoantibodies were tested for neurite outgrowth inhibition in N2A neuroblastoma cells or the ability to modulate Ca2+ release in HL-1 atrial cardiomyocytes or in endothelial cells. The stability of depolarizing autoantibodies was investigated by heat treatment (56°C × 30 minutes) or following prolonged exposure to the pro-protein convertase, furin. Gel filtration of active depolarizing autoantibodies was performed to determine the apparent molecular mass of peak neurotoxicity associated with the autoantibodies. Diabetic depression (n = 21) autoantibodies caused significantly greater mean depolarization in neuroblastoma cells (P < 0.01) compared to autoantibodies in diabetic (n = 15) or non-diabetic (n = 11) patients without depression. Depolarizing autoantibodies caused significantly more (P=0.011) inhibition of neurite outgrowth in neuroblastoma cells than non-depolarizing autoantibodies (n = 10) and they evoked sustained, global intracellular Ca2+ release in atrial cardiomyocytes or in endothelial cells. A subset of older diabetic patients suffering with a cluster of nephropathy, non-ischemic cardiomyopathy and/or depression demonstrated the presence of stable light chain dimers having apparent MW of 46 kD and associated with peak neurotoxicity in neuroblastoma cells. These data suggest that autoantibodies in older adult diabetic depression cause long-lasting depolarization in hippocampal neurons including adult dentate gyrus neural progenitor cells. The autoantibodies may impair adult dentate gyrus neurogenesis associated with treatment-refractory depression via several mechanisms including suppression of neurite outgrowth, and alteration of membrane excitability. Stable, toxic light chain autoantibody components may contribute to a cluster of severe (late-onset) complications characterized by dysfunction in highly vascularized tissues.

Conditioned Medium Derived from Neural Progenitor Cells Induces Long-term Post-ischemic Neuroprotection, Sustained Neurological Recovery, Neurogenesis, and Angiogenesis.

Adult neural progenitor cells (NPCs) induce post-ischemic long-term neuroprotection and brain remodeling by releasing of survival- and plasticity-promoting mediators. To evaluate whether secreted factors may mimic neuroprotective and restorative effects of NPCs, we exposed male C57BL6 mice to focal cerebral ischemia and intravenously applied conditioned medium (CM) derived from subventricular zone NPCs. CM dose-dependently reduced infarct volume and brain leukocyte infiltration after 48h when delivered up to 12h after focal cerebral ischemia. Neuroprotection persisted in the post-acute stroke phase yielding enhanced neurological recovery that lasted throughout the 28-day observation period. Increased Bcl-2, phosphorylated Akt and phosphorylated STAT-3 abundance, and reduced caspase-3 activity and Bax abundance were noted in ischemic brains of CM-treated mice at 48h post-stroke, indicative of enhanced cell survival signaling. Long-term neuroprotection was associated with increased brain glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) concentrations at 28days resulting in increased neurogenesis and angiogenesis. The observation that NPC-derived CM induces sustained neuroprotection and neurological recovery suggests that cell transplantation may be dispensable when secreted factors are instead administered.

Stem Cell Therapy ‒ Approach for Multiple Sclerosis Treatment

Context: Multiple sclerosis (MS) is an autoimmune and inflammatory disease that affects the central nervous system (CNS). In MS, activated T-cells for self-antigens, such as myelin, attack erroneous targets in the CNS and result in axonal demyelination and neurological disability. Stem cell (SC) therapy has potential applications in treating neurological disorders. Evidence Acquisition: The reasoning for use of SCs from different sources, as a therapeutic option in MS, arose from the expectation that they have the capacity to remyelinate and differentiate into oligodendrocyte precursor cells. Many SC types are under testing for treating MS and, the most common, are neural SC (NSC), embryonic SC (ESC), mesenchymal SC (MSC) and hematopoietic SC (HSC). Results: The NSCs, namely adult NSCs, bone marrow-derived-NSCs and neural progenitor cells, are capable of differentiation into oligodendrocytes and induce remyelination. The MSCs influence on the rate of repair of all endogenous progenitors. The autologous HSC transplantation is an option in cases that do not respond to standard therapy and also meliorate the symptoms and limit progression of disease. The ESCs have shown neuroprotection in cases of MS, through a yet unclear immunosuppression mechanism. Conclusions: Recently, cell transplantation has introduced a novel approach for treatment of neurological disorders, such as MS. Therefore, focusing on safety issues, while bridging from the basic SC sciences to the clinical transplantation trials, has a crucial role in cellular therapy programs. This review will discuss in detail the experimental and clinical use of these SC populations and their probably mechanisms in the treatment of multiple sclerosis.

PAX6 expression may be protective against dopaminergic cell loss in Parkinson's disease.

The transcription factor Pax6 is a well-accepted neurogenic determinant during development, in adult neural progenitor cells and in acute brain injury models. In the adult brain Pax6 is expressed in selective populations of dopaminergic neurons, and thus may have a role to play in Parkinson's disease (PD). This study looked at post-mortem tissue from patients with PD and in particular the substantia nigra which showed a reduced number of PAX6+ cells compared to age and sex matched control tissue. In an animal model of PD, there was an early transient increase in the number of SN Pax6+ cells at the time of cell loss through apoptosis. Finally we showed that an over-expression of Pax6 in SH-SY5Y cells treated with PD relevant neurotoxins, resulted in an increase in cell survival and a reduction in markers of apoptosis and oxidative stress. These results suggest that Pax6 may have a role to play in the loss of dopaminergic neurons in PD.

Doublecortin (DCX) is not Essential for Survival and Differentiation of Newborn Neurons in the Adult Mouse Dentate Gyrus.

In the adult brain, expression of the microtubule-associated protein Doublecortin (DCX) is associated with neural progenitor cells (NPCs) that give rise to new neurons in the dentate gyrus. Many studies quantify the number of DCX-expressing cells as a proxy for the level of adult neurogenesis, yet no study has determined the effect of removing DCX from adult hippocampal NPCs. Here, we use a retroviral and inducible mouse transgenic approach to either knockdown or knockout DCX from adult NPCs in the dentate gyrus and examine how this affects cell survival and neuronal maturation. Our results demonstrate that shRNA-mediated knockdown of DCX or Cre-mediated recombination in floxed DCX mice does not alter hippocampal neurogenesis and does not change the neuronal fate of the NPCs. Together these findings show that the survival and maturation of adult-generated hippocampal neurons does not require DCX.