Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.

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Farioli-Vecchioli, Stefano; Mattera, Andrea; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca; Saraulli, Daniele; Costanzi, Marco; Cestari, Vincenzo; Rouault, Jean-Pierre; Tirone, Felice

2014-07-01

Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis. © 2014 AlphaMed Press.

Detrimental effects of physical inactivity on neurogenesis

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Trenton Lippert

2016-01-01

Full Text Available Patients diagnosed with neurological disorders exhibit a variety of physical and psychiatric symptoms, including muscle atrophy, general immobility, and depression. Patients who participate in physical rehabilitation at times show unexpected clinical improvement, which includes diminished depression and other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for central nervous system (CNS disorders, transplantation of exogenous stem cells, and enhancing the endogenous neurogenesis. The latter therapy utilizes a natural method of re-innervating the injured brain, which may mend neurological impairments. In this study, we examine how inactivity-induced atrophy, using the hindlimb suspension model, alters neurogenesis in rats. The hypothesis is that inactivity inhibits neurogenesis by decreasing circulation growth or trophic factors, such as vascular endothelial growth or neurotrophic factors. The restriction modifies neurogenesis and stem cell differentiation in the CNS, the stem cell microenvironment is examined by the trophic and growth factors, including stress-related proteins. Despite growing evidence revealing the benefits of "increased" exercise on neurogenesis, the opposing theory involving "physical inactivity," which simulates pathological states, continues to be neglected. This novel theory will allow us to explore the effects on neurogenesis by an intransigent stem cell microenvironment likely generated by inactivity. 5-bromo-2-deoxyuridine labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid, and brain levels of trophic factors, growth factors, and stress-related proteins are suggested identifiers of neurogenesis, while evaluation of spontaneous movements will give insight into the psychomotor effects of inactivity. Investigations devised to show how in vivo stimulation, or lack thereof, affects the stem cell microenvironment are necessary to establish

MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis.

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Zhao, Chunnian; Sun, GuoQiang; Ye, Peng; Li, Shengxiu; Shi, Yanhong

2013-01-01

MicroRNAs have important functions in the nervous system through post-transcriptional regulation of neurogenesis genes. Here we show that microRNA let-7d, which has been implicated in cocaine addiction and other neurological disorders, targets the neural stem cell regulator TLX. Overexpression of let-7d in vivo reduced neural stem cell proliferation and promoted premature neuronal differentiation and migration, a phenotype similar to those induced by TLX knockdown or overexpression of its negatively-regulated target, microRNA-9. We found a let-7d binding sequence in the tlx 3' UTR and demonstrated that let-7d reduced TLX expression levels in neural stem cells, which in turn, up-regulated miR-9 expression. Moreover, co-expression of let-7d and TLX lacking its 3' UTR in vivo restored neural stem cell proliferation and reversed the premature neuronal differentiation and migration. Therefore, manipulating let-7d and its downstream targets could be a novel strategy to unravel neurogenic signaling pathways and identify potential interventions for relevant neurological disorders.

Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.

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Taupin, Philippe

2009-05-01

The application is in the field of adult neurogenesis, neural stem cells and cellular therapy. It aims to characterize the activity of nootropic agents on adult neurogenesis in vitro. Nootropic agents are substances improving cognitive and mental abilities. AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and nootropic agents were assessed for the potential to differentiate human neural progenitor and stem cells into neuronal cells in vitro. They were also tested for their behavioural activity on the novel object recognition task. AMPA, piracetam, FK-960 and SGS-111 induce and stimulate neuronal differentiation of human-derived neural progenitor and stem cells. SGS-111 increases the number of visits to the novel object. The neurogenic activity of piracetam and SGS-111 is mediated through AMPA receptor. The neurogenic activity of SGS-111 may contribute and play a role in its nootropic activity. These results suggest that nootropic agents may elicit some of their effects through their neurogenic activity. The application claims the use of nootropic agents for their neurogenic activity and for the treatment of neurological diseases, disorders and injuries, by stimulating or increasing the generation of neuronal cells in the adult brain.

Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing.

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Hochgerner, Hannah; Zeisel, Amit; Lönnerberg, Peter; Linnarsson, Sten

2018-02-01

The dentate gyrus of the hippocampus is a brain region in which neurogenesis persists into adulthood; however, the relationship between developmental and adult dentate gyrus neurogenesis has not been examined in detail. Here we used single-cell RNA sequencing to reveal the molecular dynamics and diversity of dentate gyrus cell types in perinatal, juvenile, and adult mice. We found distinct quiescent and proliferating progenitor cell types, linked by transient intermediate states to neuroblast stages and fully mature granule cells. We observed shifts in the molecular identity of quiescent and proliferating radial glia and granule cells during the postnatal period that were then maintained through adult stages. In contrast, intermediate progenitor cells, neuroblasts, and immature granule cells were nearly indistinguishable at all ages. These findings demonstrate the fundamental similarity of postnatal and adult neurogenesis in the hippocampus and pinpoint the early postnatal transformation of radial glia from embryonic progenitors to adult quiescent stem cells.

Neurogenesis and The Effect of Antidepressants

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Philippe Taupin

2006-01-01

Full Text Available The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs reside in the adult central nervous system (CNS suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

Neurogenesis and the Effect of Antidepressants

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Philippe Taupin

2006-01-01

Full Text Available The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs reside in the adult central nervous system (CNS suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

Neurogenesis and Alzheimer's Disease

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Philippe Taupin

2006-01-01

Full Text Available Alzheimer’s disease (AD is a neurodegenerative disease, characterized in the brain by amyloid plaque deposits and neurofibrillary tangles. It is the most common form of dementia among older people. There is at present no cure for AD, and current treatments consist mainly in drug therapy. Potential therapies for AD involve gene and cellular therapy. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs reside in the adult central nervous system (CNS provide new opportunities for cellular therapy in the CNS, particularly for AD, and to better understand brain physiopathology. Hence, researchers have aimed at characterizing neurogenesis in patients with AD. Studies show that neurogenesis is increased in these patients, and in animal models of AD. The effect of drugs used to treat AD on neurogenesis is currently being investigated, to identify whether neurogenesis contributes to their therapeutic activities.

Neurogenesis and Alzheimer's Disease

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Philippe Taupin

2006-01-01

Full Text Available Alzheimer's disease (AD is a neurodegenerative disease, characterized in the brain by amyloid plaque deposits and neurofibrillary tangles. It is the most common form of dementia among older people. There is at present no cure for AD, and current treatments consist mainly in drug therapy. Potential therapies for AD involve gene and cellular therapy. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs reside in the adult central nervous system (CNS provide new opportunities for cellular therapy in the CNS, particularly for AD, and to better understand brain physiopathology. Hence, researchers have aimed at characterizing neurogenesis in patients with AD. Studies show that neurogenesis is increased in these patients, and in animal models of AD. The effect of drugs used to treat AD on neurogenesis is currently being investigated, to identify whether neurogenesis contributes to their therapeutic activities.

Stimulation of angiogenesis, neurogenesis and regeneration by side population cells from dental pulp.

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Ishizaka, Ryo; Hayashi, Yuki; Iohara, Koichiro; Sugiyama, Masahiko; Murakami, Masashi; Yamamoto, Tsubasa; Fukuta, Osamu; Nakashima, Misako

2013-03-01

Mesenchymal stem cells (MSCs) have been used for cell therapy in various experimental disease models. However, the regenerative potential of MSCs from different tissue sources and the influence of the tissue niche have not been investigated. In this study, we compared the regenerative potential of dental pulp, bone marrow and adipose tissue-derived CD31(-) side population (SP) cells isolated from an individual porcine source. Pulp CD31(-) SP cells expressed the highest levels of angiogenic/neurotrophic factors and had the highest migration activity. Conditioned medium from pulp CD31(-) SP cells produced potent anti-apoptotic activity and neurite outgrowth, compared to those from bone marrow and adipose CD31(-) SP cells. Transplantation of pulp CD31(-) SP cells in a mouse hindlimb ischemia model produced higher blood flow and capillary density than transplantation of bone marrow and adipose CD31(-) SP cells. Motor function recovery and infarct size reduction were greater with pulp CD31(-) SP cells. Pulp CD31(-) SP cells induced maximal angiogenesis, neurogenesis and pulp regeneration in ectopic transplantation models compared to other tissue sources. These results demonstrate that pulp stem cells have higher angiogenic, neurogenic and regenerative potential and may therefore be superior to bone marrow and adipose stem cells for cell therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Abrogated inflammatory response promotes neurogenesis in a murine model of Japanese encephalitis.

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Sulagna Das

2011-03-01

Full Text Available Japanese encephalitis virus (JEV induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline.Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used.This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors.

14-3-3 Proteins in Brain Development: Neurogenesis, Neuronal Migration and Neuromorphogenesis

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Brett Cornell

2017-10-01

Full Text Available The 14-3-3 proteins are a family of highly conserved, multifunctional proteins that are highly expressed in the brain during development. Cumulatively, the seven 14-3-3 isoforms make up approximately 1% of total soluble brain protein. Over the last decade, evidence has accumulated implicating the importance of the 14-3-3 protein family in the development of the nervous system, in particular cortical development, and have more recently been recognized as key regulators in a number of neurodevelopmental processes. In this review we will discuss the known roles of each 14-3-3 isoform in the development of the cortex, their relation to human neurodevelopmental disorders, as well as the challenges and questions that are left to be answered. In particular, we focus on the 14-3-3 isoforms and their involvement in the three key stages of cortical development; neurogenesis and differentiation, neuronal migration and neuromorphogenesis and synaptogenesis.

Neurogenesis and Increase in Differentiated Neural Cell Survival via Phosphorylation of Akt1 after Fluoxetine Treatment of Stem Cells

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Anahita Rahmani

2013-01-01

Full Text Available Fluoxetine (FLX is a selective serotonin reuptake inhibitor (SSRI. Its action is possibly through an increase in neural cell survival. The mechanism of improved survival rate of neurons by FLX may relate to the overexpression of some kinases such as Akt protein. Akt1 (a serine/threonine kinase plays a key role in the modulation of cell proliferation and survival. Our study evaluated the effects of FLX on mesenchymal stem cell (MSC fate and Akt1 phosphorylation levels in MSCs. Evaluation tests included reverse transcriptase polymerase chain reaction, western blot, and immunocytochemistry assays. Nestin, MAP-2, and β-tubulin were detected after neurogenesis as neural markers. Ten μM of FLX upregulated phosphorylation of Akt1 protein in induced hEnSC significantly. Also FLX did increase viability of these MSCs. Continuous FLX treatment after neurogenesis elevated the survival rate of differentiated neural cells probably by enhanced induction of Akt1 phosphorylation. This study addresses a novel role of FLX in neurogenesis and differentiated neural cell survival that may contribute to explaining the therapeutic action of fluoxetine in regenerative pharmacology.

D-serine increases adult hippocampal neurogenesis

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Sebastien eSultan

2013-08-01

Full Text Available Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells

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Jingjun Li

2016-09-01

Full Text Available Neural stem cells and progenitor cells (NPCs are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases.

Neurogenesis dan Faktor-Faktor yang Berpengaruh

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Ria Puspitawati

2015-09-01

Full Text Available Development of nerve tissue is known as neurogenesis. Vertebrate neve system has various functional capabilities from sensory perception, motor coordination, to the ability in producing motivation, spatial abilities, learning and memorizing due to various cell types that accurately connected and interact to each other. The connections between various nerve cells are continuously developed from the embryonic time until the early period of life. Recent studies have showed that neurogenesis in certain regions of nerve tissue can still be found in adults. This article reviews the cellular mechanism of neurogenesis and conditions that have role in the process.

The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis.

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Stephen N Sansom

2009-06-01

Full Text Available Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells

TLX: A master regulator for neural stem cell maintenance and neurogenesis.

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Islam, Mohammed M; Zhang, Chun-Li

2015-02-01

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development. Copyright © 2014 Elsevier B.V. All rights reserved.

The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment.

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Donega, Vanessa; van Velthoven, Cindy T J; Nijboer, Cora H; Kavelaars, Annemieke; Heijnen, Cobi J

2013-05-01

Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia-ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategies. The latest findings indicate that stem cells represent a novel therapeutic possibility to improve outcome in models of neonatal encephalopathy. Transplanted stem cells secrete factors that stimulate and maintain neurogenesis, thereby increasing cell proliferation, neuronal differentiation, and functional integration. Understanding the molecular and cellular mechanisms underlying neurogenesis after an insult is crucial for developing tools to enhance the neurogenic capacity of the brain. The aim of this review is to discuss the endogenous capacity of the neonatal brain to regenerate after a cerebral ischemic insult. We present an overview of the molecular and cellular mechanisms underlying endogenous regenerative processes during development as well as after a cerebral ischemic insult. Furthermore, we will consider the potential to use stem cell transplantation as a means to boost endogenous neurogenesis and restore brain function.

Galectin-1 is expressed in early-type neural progenitor cells and down-regulates neurogenesis in the adult hippocampus

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Imaizumi Yoichi

2011-01-01

Full Text Available Abstract Background In the adult mammalian brain, neural stem cells (NSCs proliferate in the dentate gyrus (DG of the hippocampus and generate new neurons throughout life. A multimodal protein, Galectin-1, is expressed in neural progenitor cells (NPCs and implicated in the proliferation of the NPCs in the DG. However, little is known about its detailed expression profile in the NPCs and functions in adult neurogenesis in the DG. Results Our immunohistochemical and morphological analysis showed that Galectin-1 was expressed in the type 1 and 2a cells, which are putative NSCs, in the subgranular zone (SGZ of the adult mouse DG. To study Galectin-1's function in adult hippocampal neurogenesis, we made galectin-1 knock-out mice on the C57BL6 background and characterized the effects on neurogenesis. In the SGZ of the galectin-1 knock-out mice, increased numbers of type 1 cells, DCX-positive immature progenitors, and NeuN-positive newborn neurons were observed. Using triple-labeling immunohistochemistry and morphological analyses, we found that the proliferation of the type-1 cells was increased in the SGZ of the galectin-1 knock-out mice, and we propose that this proliferation is the mechanism for the net increase in the adult neurogenesis in these knock-out mice DG. Conclusions Galectin-1 is expressed in the neural stem cells and down-regulates neurogenesis in the adult hippocampus.

COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal Cxcr4 expression.

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Parisot, Joséphine; Flore, Gemma; Bertacchi, Michele; Studer, Michèle

2017-06-01

Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages, and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it in either granule cell progenitors or granule neurons. Loss of COUP-TFI function in progenitors leads to decreased granule cell proliferative activity, precocious differentiation and increased apoptosis, resulting in a severe DG growth defect in adult mice. COUP-TFI-deficient cells express high levels of the chemokine receptor Cxcr4 and migrate abnormally, forming heterotopic clusters of differentiated granule cells along their paths. Conversely, high COUP-TFI expression levels downregulate Cxcr4 expression, whereas increased Cxcr4 expression in wild-type hippocampal cells affects cell migration. Finally, loss of COUP-TFI in postmitotic cells leads to only minor and transient abnormalities, and to normal Cxcr4 expression. Together, our results indicate that COUP-TFI is required predominantly in DG progenitors for modulating expression of the Cxcr4 receptor during granule cell neurogenesis and migration. © 2017. Published by The Company of Biologists Ltd.

The neurogenic factor NeuroD1 is expressed in post-mitotic cells during juvenile and adult Xenopus neurogenesis and not in progenitor or radial glial cells.

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Laure Anne D'Amico

Full Text Available In contrast to mammals that have limited proliferation and neurogenesis capacities, the Xenopus frog exhibit a great potential regarding proliferation and production of new cells in the adult brain. This ability makes Xenopus a useful model for understanding the molecular programs required for adult neurogenesis. Transcriptional factors that control adult neurogenesis in vertebrate species undergoing widespread neurogenesis are unknown. NeuroD1 is a member of the family of proneural genes, which function during embryonic neurogenesis as a potent neuronal differentiation factor. Here, we study in detail the expression of NeuroD1 gene in the juvenile and adult Xenopus brains by in situ hybridization combined with immunodetections for proliferation markers (PCNA, BrdU or in situ hybridizations for cell type markers (Vimentin, Sox2. We found NeuroD1 gene activity in many brain regions, including olfactory bulbs, pallial regions of cerebral hemispheres, preoptic area, habenula, hypothalamus, cerebellum and medulla oblongata. We also demonstrated by double staining NeuroD1/BrdU experiments, after long post-BrdU administration survival times, that NeuroD1 gene activity was turned on in new born neurons during post-metamorphic neurogenesis. Importantly, we provided evidence that NeuroD1-expressing cells at this brain developmental stage were post-mitotic (PCNA- cells and not radial glial (Vimentin+ or progenitors (Sox2+ cells.

Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice

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Laura B. Ngwenya

2018-01-01

Full Text Available Cognitive deficits after traumatic brain injury (TBI are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI in adult mice and transplanted embryonic stem cell-derived neural progenitor cells (NPC. Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation.

Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function.

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Poulose, Shibu M; Miller, Marshall G; Scott, Tammy; Shukitt-Hale, Barbara

2017-11-01

Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plasticity, brain homeostasis, and maintenance in the central nervous system and is a crucial factor in preserving the cognitive function and repair of damaged brain cells affected by aging and brain disorders. Intrinsic factors such as aging, neuroinflammation, oxidative stress, and brain injury, as well as lifestyle factors such as high-fat and high-sugar diets and alcohol and opioid addiction, negatively affect adult neurogenesis. Conversely, many dietary components such as curcumin, resveratrol, blueberry polyphenols, sulforaphane, salvionic acid, polyunsaturated fatty acids (PUFAs), and diets enriched with polyphenols and PUFAs, as well as caloric restriction, physical exercise, and learning, have been shown to induce neurogenesis in adult brains. Although many of the underlying mechanisms by which nutrients and dietary factors affect adult neurogenesis have yet to be determined, nutritional approaches provide promising prospects to stimulate adult neurogenesis and combat neurodegenerative diseases and cognitive decline. In this review, we summarize the evidence supporting the role of nutritional factors in modifying adult neurogenesis and their potential to preserve cognitive function during aging. © 2017 American Society for Nutrition.

Aminopropyl carbazole analogues as potent enhancers of neurogenesis.

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Yoon, Hye Jin; Kong, Sun-Young; Park, Min-Hye; Cho, Yongsung; Kim, Sung-Eun; Shin, Jae-Yeon; Jung, Sunghye; Lee, Jiyoun; Farhanullah; Kim, Hyun-Jung; Lee, Jeewoo

2013-11-15

Neural stem cells are multipotent and self-renewing cells that can differentiate into new neurons and hold great promise for treating various neurological disorders including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Small molecules that can trigger neurogenesis and neuroprotection are particularly useful not only because of their therapeutic implications but also because they can provide an invaluable tool to study the mechanisms of neurogenesis. In this report, we have developed and screened 25 aminopropyl carbazole derivatives that can enhance neurogenesis of cultured neural stem cells. Among these analogues, compound 9 demonstrated an excellent proneurogenic and neuroprotective activity with no apparent toxicity. We believe that compound 9 can serve as an excellent lead to develop various analogues and to study the underlying mechanisms of neurogenesis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Enhanced post-ischemic neurogenesis in aging rats

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Yao-Fang Tan

2010-08-01

Full Text Available Hippocampal neurogenesis persists in adult mammals, but its rate declines dramatically with age. Evidence indicates that experimentally-reduced levels of neurogenesis (e.g. by irradiation in young rats has profound influence on cognition as determined by learning and memory tests. In the present study we asked whether in middle-aged, 10-13 months old rats, cell production can be restored towards the level present in young rats. To manipulate neurogenesis we induced bilateral carotid occlusion with hypotension. This procedure is known to increase neurogenesis in young rats, presumably in a compensatory manner, but until now, has never been tested in aging rats. Cell production was measured at 10, 35 and 90 days after ischemia. The results indicate that neuronal proliferation and differentiation can be transiently restored in middle-aged rats. Furthermore, the effects are more pronounced in the dorsal as opposed to ventral hippocampus thus restoring the dorso-ventral gradient seen in younger rats. Our results support previous findings showing that some of the essential features of the age-dependent decline in neurogenesis are reversible. Thus, it may be possible to manipulate neurogenesis and improve learning and memory in old age.

Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

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Eleni Paizanis

2007-01-01

Full Text Available There is a growing body of evidence that neural stem cells reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone, where it is controlled by several trophic factors and neuroactive molecules. Neurogenesis is involved in processes such as learning and memory and accumulating evidence implicates hippocampal neurogenesis in the physiopathology of depression. We herein review experimental and clinical data demonstrating that stress and antidepressant treatments affect neurogenesis in opposite direction in rodents. In particular, the stimulation of hippocampal neurogenesis by all types of antidepressant drugs supports the view that neuroplastic phenomena are involved in the physiopathology of depression and underlie—at least partly—antidepressant therapy.

Neurotoxic effect of 2,5-hexanedione on neural progenitor cells and hippocampal neurogenesis

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Kim, Min-Sun; Park, Hee Ra; Park, Mikyung; Kim, So Jung; Kwon, Mugil; Yu, Byung Pal; Chung, Hae Young; Kim, Hyung Sik; Kwack, Seung Jun; Kang, Tae Seok; Kim, Seung Hee; Lee, Jaewon

2009-01-01

2,5-Hexanedione (HD), a metabolite of n-hexane, causes central and peripheral neuropathy leading to motor neuron deficits. Although chronic exposure to n-hexane is known to cause gradual sensorimotor neuropathy, there are no reports on the effects of low doses of HD on neurogenesis in the central nervous system. In the current study, we explored HD toxicity in murine neural progenitor cells (NPC), primary neuronal culture and young adult mice. HD (500 nM∼50 μM) dose-dependently suppressed NPC proliferation and cell viability, and also increased the production of reactive oxygen species (ROS). HD (10 or 50 mg/kg for 2 weeks) inhibited hippocampal neuronal and NPC proliferation in 6-week-old male ICR mice, as measured by BrdU incorporation in the dentate gyrus, indicating HD impaired hippocampal neurogenesis. In addition, elevated microglial activation was observed in the hippocampal CA3 region and lateral ventricles of HD-treated mice. Lastly, HD dose-dependently decreased the viability of primary cultured neurons. Based on biochemical and histochemical evidence from both cell culture and HD-treated animals, the neurotoxic mechanisms by which HD inhibits NPC proliferation and hippocampal neurogenesis may relate to its ability to elicit an increased generation of deleterious ROS.

Reparative neurogenesis after cerebral ischemia: Clinical application prospects

Energy Technology Data Exchange (ETDEWEB)

Khodanovich, M. Yu., E-mail: khodanovich@mail.tsu.ru [Tomsk State University, Research Institute of Biology and Biophysics, Laboratory of Neurobiology (Russian Federation)

2015-11-17

At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

Reparative neurogenesis after cerebral ischemia: Clinical application prospects

Science.gov (United States)

Khodanovich, M. Yu.

2015-11-01

At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

Reparative neurogenesis after cerebral ischemia: Clinical application prospects

International Nuclear Information System (INIS)

Khodanovich, M. Yu.

2015-01-01

At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors

Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function

Science.gov (United States)

Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plas...

Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later

Science.gov (United States)

Bond, Allison M.; Ming, Guo-li; Song, Hongjun

2015-01-01

Summary Adult somatic stem cells in various organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discovery five decades ago, investigations of adult neurogenesis and neural stem cells have led to an established and expanding field that has significantly influenced many facets of neuroscience, developmental biology and regenerative medicine. Here we review recent progress and focus on questions related to adult mammalian neural stem cells that also apply to other somatic stem cells. We further discuss emerging topics that are guiding the field toward better understanding adult neural stem cells and ultimately applying these principles to improve human health. PMID:26431181

Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective

Science.gov (United States)

Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.

2016-01-01

New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907

The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.

Science.gov (United States)

Rodriguez Viales, Rebecca; Diotel, Nicolas; Ferg, Marco; Armant, Olivier; Eich, Julia; Alunni, Alessandro; März, Martin; Bally-Cuif, Laure; Rastegar, Sepand; Strähle, Uwe

2015-03-01

The teleost brain has the remarkable ability to generate new neurons and to repair injuries during adult life stages. Maintaining life-long neurogenesis requires careful management of neural stem cell pools. In a genome-wide expression screen for transcription regulators, the id1 gene, encoding a negative regulator of E-proteins, was found to be upregulated in response to injury. id1 expression was mapped to quiescent type I neural stem cells in the adult telencephalic stem cell niche. Gain and loss of id1 function in vivo demonstrated that Id1 promotes stem cell quiescence. The increased id1 expression observed in neural stem cells in response to injury appeared independent of inflammatory signals, suggesting multiple antagonistic pathways in the regulation of reactive neurogenesis. Together, we propose that Id1 acts to maintain the neural stem cell pool by counteracting neurogenesis-promoting signals. © 2014 AlphaMed Press.

The role of additive neurogenesis and synaptic plasticity in a hippocampal memory model with grid-cell like input.

Directory of Open Access Journals (Sweden)

Peter A Appleby

Full Text Available Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic; neuronal turnover, where the network is of fixed size but units in the network may die and be replaced; and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus

Absence of the calcium-binding protein calretinin, not of calbindin D-28k, causes a permanent impairment of murine adult hippocampal neurogenesis

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Kiran eTodkar

2012-04-01

Full Text Available Calretinin (CR and calbindin D-28k (CB are cytosolic EF-hand Ca2+-binding proteins and function as Ca2+ buffers affecting the spatiotemporal aspects of Ca2+ transients and possibly also as Ca2+ sensors modulating signaling cascades. In the adult hippocampal circuitry, CR and CB are expressed in specific principal neurons and subsets of interneurons. In addition, CR is transiently expressed within the neurogenic dentate gyrus (DG niche. CR and CB expression during adult neurogenesis mark critical transition stages, onset of differentiation for CR and the switch to adult-like connectivity for CB. Absence of either protein during these stages in null-mutant mice may have functional consequences and contribute to some aspects of the identified phenotypes. We report the impact of CR- and CB-deficiency on the proliferation and differentiation of progenitor cells within the subgranular zone (SGZ neurogenic niche of the DG. Effects were evaluated I 2 and 4 weeks postnatally, during the transition period of the proliferative matrix to the adult state, and II in adult animals (3 months to trace possible permanent changes in adult neurogenesis. The absence of CB from differentiated DG granule cells has no retrograde effect on the proliferative activity of progenitor cells, nor affects survival or migration/differentiation of newborn neurons in the adult DG including the SGZ. On the contrary, lack of CR from immature early postmitotic granule cells causes an early loss in proliferative capacity of the SGZ that is maintained into adult age, when it has a further impact on the migration/survival of newborn granule cells. The transient CR expression at the onset of adult neurogenesis differentiation may thus have two functions: I to serve as a self-maintenance signal for the pool of cells at the same stage of neurogenesis contributing to their survival/differentiation, and II it may contribute to retrograde signaling required for maintenance of the progenitor

Andrographolide Stimulates Neurogenesis in the Adult Hippocampus

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Lorena Varela-Nallar

2015-01-01

Full Text Available Andrographolide (ANDRO is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β, a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected.

EVA1A/TMEM166 Regulates Embryonic Neurogenesis by Autophagy

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Mengtao Li

2016-03-01

Full Text Available Self-renewal and differentiation of neural stem cells is essential for embryonic neurogenesis, which is associated with cell autophagy. However, the mechanism by which autophagy regulates neurogenesis remains undefined. Here, we show that Eva1a/Tmem166, an autophagy-related gene, regulates neural stem cell self-renewal and differentiation. Eva1a depletion impaired the generation of newborn neurons, both in vivo and in vitro. Conversely, overexpression of EVA1A enhanced newborn neuron generation and maturation. Moreover, Eva1a depletion activated the PIK3CA-AKT axis, leading to the activation of the mammalian target of rapamycin and the subsequent inhibition of autophagy. Furthermore, addition of methylpyruvate to the culture during neural stem cell differentiation rescued the defective embryonic neurogenesis induced by Eva1a depletion, suggesting that energy availability is a significant factor in embryonic neurogenesis. Collectively, these data demonstrated that EVA1A regulates embryonic neurogenesis by modulating autophagy. Our results have potential implications for understanding the pathogenesis of neurodevelopmental disorders caused by autophagy dysregulation.

TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

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Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

2013-12-15

TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

Sex steroids and neurogenesis.

Science.gov (United States)

Heberden, Christine

2017-10-01

The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives. Copyright © 2017 Elsevier Inc. All rights reserved.

Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

International Nuclear Information System (INIS)

Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

2015-01-01

Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3 + apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB + interneurons, although the number of reelin + interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of cholinergic

Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

Energy Technology Data Exchange (ETDEWEB)

Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Yoshida, Toshinori [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

2015-09-15

Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

Opposing Effects of α2- and β-Adrenergic Receptor Stimulation on Quiescent Neural Precursor Cell Activity and Adult Hippocampal Neurogenesis

Science.gov (United States)

Prosper, Boris W.; Marathe, Swanand; Husain, Basma F. A.; Kernie, Steven G.; Bartlett, Perry F.; Vaidya, Vidita A.

2014-01-01

Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis. PMID:24922313

Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

International Nuclear Information System (INIS)

Jenrow, Kenneth A; Brown, Stephen L; Liu, Jianguo; Kolozsvary, Andrew; Lapanowski, Karen; Kim, Jae Ho

2010-01-01

Sublethal doses of whole brain irradiation (WBI) are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ) of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS) has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE) inhibitor, ramipril, as a mitigator of radiation injury in this context. Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks. Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats. Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory disruption of neurogenic signaling within SGZ microenvironment, and

Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate-induced injury is lost by middle age

OpenAIRE

Hattiangady, Bharathi; Rao, Muddanna S.; Shetty, Ashok K.

2008-01-01

A remarkable up-regulation of neurogenesis through increased proliferation of neural stem/progenitor cells (NSCs) is a well-known plasticity displayed by the young dentate gyrus (DG) following brain injury. To ascertain whether this plasticity is preserved during aging, we quantified DG neurogenesis in the young adult, middle-aged and aged F344 rats after kainic acid induced hippocampal injury. Measurement of new cells that are added to the dentate granule cell layer (GCL) between post-injury...

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro.

Science.gov (United States)

Morales-García, Jose A; de la Fuente Revenga, Mario; Alonso-Gil, Sandra; Rodríguez-Franco, María Isabel; Feilding, Amanda; Perez-Castillo, Ana; Riba, Jordi

2017-07-13

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

Science.gov (United States)

Galea, L A M; Wainwright, S R; Roes, M M; Duarte-Guterman, P; Chow, C; Hamson, D K

2013-11-01

The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex- and experience-dependent way. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely unexpected because the physiology of males and females is different, with the most notable difference being that females gestate and nurse the offspring. Furthermore, reproductive experience (i.e. pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression, and the present review provides early evidence of the functional links between the hormonal modulation of neurogenesis that may contribute to the regulation of cognition and stress. © 2013 British Society for Neuroendocrinology.

Alternative Splicing in Neurogenesis and Brain Development.

Science.gov (United States)

Su, Chun-Hao; D, Dhananjaya; Tarn, Woan-Yuh

2018-01-01

Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

Alternative Splicing in Neurogenesis and Brain Development

Directory of Open Access Journals (Sweden)

Chun-Hao Su

2018-02-01

Full Text Available Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice.

Science.gov (United States)

Kuzumaki, Naoko; Ikegami, Daigo; Imai, Satoshi; Narita, Michiko; Tamura, Rie; Yajima, Marie; Suzuki, Atsuo; Miyashita, Kazuhiko; Niikura, Keiichi; Takeshima, Hideyuki; Ando, Takayuki; Ushijima, Toshikazu; Suzuki, Tsutomu; Narita, Minoru

2010-09-01

A variety of mechanisms that contribute to the accumulation of age-related damage and the resulting brain dysfunction have been identified. Recently, decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. However, the molecular mechanism of decreased neurogenesis with aging is still unclear. In the present study, we investigated whether aging decreases neurogenesis accompanied by the activation of microglia and astrocytes, which increases the expression of IL-1beta in the hippocampus, and whether in vitro treatment with IL-1beta in neural stem cells directly impairs neurogenesis. Ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were increased in the dentate gyrus of the hippocampus of 28-month-old mice. Furthermore, the mRNA level of IL-1beta was significantly increased without related histone modifications. Moreover, a significant increase in lysine 9 on histone H3 (H3K9) trimethylation at the promoter of NeuroD (a neural progenitor cell marker) was observed in the hippocampus of aged mice. In vitro treatment with IL-1beta in neural stem cells prepared from whole brain of E14.5 mice significantly increased H3K9 trimethylation at the NeuroD promoter. These findings suggest that aging may decrease hippocampal neurogenesis via epigenetic modifications accompanied by the activation of microglia and astrocytes with the increased expression of IL-1beta in the hippocampus.

Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis.

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Valentina Tosetti

Full Text Available The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA Sox2 overlapping transcript (Sox2OT plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE, and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT.

Stage-dependent alterations of progenitor cell proliferation and neurogenesis in an animal model of Wernicke-Korsakoff syndrome.

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Vetreno, Ryan P; Klintsova, Anna; Savage, Lisa M

2011-05-19

Alcohol-induced Wernicke-Korsakoff syndrome (WKS) culminates in bilateral diencephalic lesion and severe amnesia. Using the pyrithiamine-induced thiamine deficiency (PTD) animal paradigm of WKS, our laboratory has demonstrated hippocampal dysfunction in the absence of gross anatomical pathology. Extensive literature has revealed reduced hippocampal neurogenesis following a neuropathological insult, which might contribute to hippocampus-based learning and memory impairments. Thus, the current investigation was conducted to determine whether PTD treatment altered hippocampal neurogenesis in a stage-dependent fashion. Male Sprague-Dawley rats were assigned to one of 4 stages of thiamine deficiency based on behavioral symptoms: pre-symptomatic stage, ataxic stage, early post-opisthotonus stage, or the late post-opisthotonus stage. The S-phase mitotic marker 5'-bromo-2'-deoxyuridine (BrdU) was administered at the conclusion of each stage following thiamine restoration and subjects were perfused 24 hours or 28 days after BrdU to assess cellular proliferation or neurogenesis and survival, respectively. Dorsal hippocampal sections were immunostained for BrdU (proliferating cell marker), NeuN (neurons), GFAP (astrocytes), Iba-1 (microglia), and O4 (oligodendrocytes). The PTD treatment increased progenitor cell proliferation and survival during the early post-opisthotonus stage. However, levels of neurogenesis were reduced during this stage as well as the late post-opisthotonus stage where there was also an increase in astrocytogenesis. The diminished numbers of newly generated neurons (BrdU/NeuN co-localization) was paralleled by increased BrdU cells that did not co-localize with any of the phenotypic markers during these later stages. These data demonstrate that long-term alterations in neurogenesis and gliogenesis might contribute to the observed hippocampal dysfunction in the PTD model and human WKS. Published by Elsevier B.V.

Prion diseases and adult neurogenesis: how do prions counteract the brain's endogenous repair machinery?

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Relaño-Ginés, Aroa; Lehmann, Sylvain; Crozet, Carole

2014-01-01

Scientific advances in stem cell biology and adult neurogenesis have raised the hope that neurodegenerative disorders could benefit from stem cell-based therapy. Adult neurogenesis might be part of the physiological regenerative process, however it might become impaired by the disease's mechanism and therefore contribute to neurodegeneration. In prion disorders this endogenous repair system has rarely been studied. Whether adult neurogenesis plays a role or not in brain repair or in the propagation of prion pathology remains unclear. We have recently investigated the status of adult neural stem cells isolated from prion-infected mice. We were able to show that neural stem cells accumulate and replicate prions thus resulting in an alteration of their neuronal destiny. We also reproduced these results in adult neural stem cells, which were infected in vitro. The fact that endogenous adult neurogenesis could be altered by the accumulation of misfolded prion protein represents another great challenge. Inhibiting prion propagation in these cells would thus help the endogenous neurogenesis to compensate for the injured neuronal system. Moreover, understanding the endogenous modulation of the neurogenesis system would help develop effective neural stem cell-based therapies.

The Role of Astrocytes in the Generation, Migration, and Integration of New Neurons in the Adult Olfactory Bulb

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Gengatharan, Archana; Bammann, Rodrigo R.; Saghatelyan, Armen

2016-01-01

In mammals, new neurons in the adult olfactory bulb originate from a pool of neural stem cells in the subventricular zone of the lateral ventricles. Adult-born cells play an important role in odor information processing by adjusting the neuronal network to changing environmental conditions. Olfactory bulb neurogenesis is supported by several non-neuronal cells. In this review, we focus on the role of astroglial cells in the generation, migration, integration, and survival of new neurons in the adult forebrain. In the subventricular zone, neural stem cells with astrocytic properties display regional and temporal specificity when generating different neuronal subtypes. Non-neurogenic astrocytes contribute to the establishment and maintenance of the neurogenic niche. Neuroblast chains migrate through the rostral migratory stream ensheathed by astrocytic processes. Astrocytes play an important regulatory role in neuroblast migration and also assist in the development of a vasculature scaffold in the migratory stream that is essential for neuroblast migration in the postnatal brain. In the olfactory bulb, astrocytes help to modulate the network through a complex release of cytokines, regulate blood flow, and provide metabolic support, which may promote the integration and survival of new neurons. Astrocytes thus play a pivotal role in various processes of adult olfactory bulb neurogenesis, and it is likely that many other functions of these glial cells will emerge in the near future. PMID:27092050

Adult hippocampal neurogenesis in natural populations of mammals.

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Amrein, Irmgard

2015-05-01

This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Putative adult neurogenesis in two domestic pigeon breeds (Columba livia domestica): racing homer versus utility carneau pigeons.

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Mazengenya, Pedzisai; Bhagwandin, Adhil; Nkomozepi, Pilani; Manger, Paul R; Ihunwo, Amadi O

2017-07-01

Generation of neurons in the brains of adult birds has been studied extensively in the telencephalon of song birds and few studies are reported on the distribution of PCNA and DCX in the telencephalon of adult non-song learning birds. We report here on adult neurogenesis throughout the brains of two breeds of adult domestic pigeons (Columba livia domestica), the racing homer and utility carneau using endogenous immunohistochemical markers proliferating cell nuclear antigen (PCNA) for proliferating cells and doublecortin (DCX) for immature and migrating neurons. The distribution of PCNA and DCX immunoreactivity was very similar in both pigeon breeds with only a few minor differences. In both pigeons, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, walls of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and cerebellum. Generally, the olfactory bulbs and telencephalon had more PCNA and DCX cells than other regions. Two proliferative hotspots were evident in the dorsal and ventral poles of the lateral ventricles. PCNA- and DCX-immunoreactive cells migrated radially from the walls of the lateral ventricle into the parenchyma. In most telencephalic regions, the density of PCNA- and DCX-immunoreactive cells increased from rostral to caudal, except in the mesopallium where the density decreased from rostral to middle levels and then increased caudally. DCX immunoreactivity was more intense in fibres than in cell bodies and DCX-immunoreactive cells included small granular cells, fusiform bipolar cells, large round and or polygonal multipolar cells. The similarity in the distribution of proliferating cells and new neurons in the telencephalon of the two breeds of pigeons may suggest that adult neurogenesis is a conserved trait as an ecological adaptation irrespective of body size.

Putative adult neurogenesis in two domestic pigeon breeds (Columba livia domestica: racing homer versus utility carneau pigeons

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Pedzisai Mazengenya

2017-01-01

Full Text Available Generation of neurons in the brains of adult birds has been studied extensively in the telencephalon of song birds and few studies are reported on the distribution of PCNA and DCX in the telencephalon of adult non-song learning birds. We report here on adult neurogenesis throughout the brains of two breeds of adult domestic pigeons (Columba livia domestica, the racing homer and utility carneau using endogenous immunohistochemical markers proliferating cell nuclear antigen (PCNA for proliferating cells and doublecortin (DCX for immature and migrating neurons. The distribution of PCNA and DCX immunoreactivity was very similar in both pigeon breeds with only a few minor differences. In both pigeons, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, walls of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and cerebellum. Generally, the olfactory bulbs and telencephalon had more PCNA and DCX cells than other regions. Two proliferative hotspots were evident in the dorsal and ventral poles of the lateral ventricles. PCNA- and DCX-immunoreactive cells migrated radially from the walls of the lateral ventricle into the parenchyma. In most telencephalic regions, the density of PCNA- and DCX-immunoreactive cells increased from rostral to caudal, except in the mesopallium where the density decreased from rostral to middle levels and then increased caudally. DCX immunoreactivity was more intense in fibres than in cell bodies and DCX-immunoreactive cells included small granular cells, fusiform bipolar cells, large round and or polygonal multipolar cells. The similarity in the distribution of proliferating cells and new neurons in the telencephalon of the two breeds of pigeons may suggest that adult neurogenesis is a conserved trait as an ecological adaptation irrespective of body size.

Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis

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Ryo Tamaki

2017-01-01

Full Text Available Endogenous neurogenesis can arise from a variety of physiological stimuli including exercise, learning, or “enriched environment” as well as pathological conditions such as ischemia, epilepsy or cortical spreading depression. Whether all these conditions use a common trigger to set off endogenous neurogenesis is yet unclear. We hypothesized that cortical spreading depression (CSD induces neurogenesis in the cerebral cortex and dentate gyrus after cerebral venous ischemia. Forty-two Wistar rats alternatively underwent sham operation (Sham, induction of ten CSDs or venous ischemia provoked via occlusion of two adjacent superficial cortical vein followed by ten induced CSDs (CSD + 2-VO. As an additional control, 15 naïve rats received no intervention except 5-bromo-2′-deoxyuridine (BrdU treatment for 7 days. Sagittal brain slices (40 μm thick were co-stained for BrdU and doublecortin (DCX; new immature neuronal cells on day 9 or NeuN (new mature neuronal cells on day 28. On day 9 after sham operation, cell proliferation and neurogenesis occurred in the cortex in rats. The sole induction of CSD had no effect. But on days 9 and 28, more proliferating cells and newly formed neurons in the ipsilateral cortex were observed in rats subjected to CSD + 2VO than in rats subjected to sham operation. On days 9 and 28, cell proliferation and neurogenesis in the ipsilateral dentate gyrus was increased in sham-operated rats than in naïve rats. Our data supports the hypothesis that induced cortical neurogenesis after CSD + 2-VO is a direct effect of ischemia, rather than of CSD alone.

Neurogenesis and brain injury: managing a renewable resource for repair

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Hallbergson, Anna F.; Gnatenco, Carmen; Peterson, Daniel A.

2003-01-01

The brain shows limited ability to repair itself, but neurogenesis in certain areas of the adult brain suggests that neural stem cells may be used for structural brain repair. It will be necessary to understand how neurogenesis in the adult brain is regulated to develop strategies that harness neural stem cells for therapeutic use.

Age-dependent kinetics of dentate gyrus neurogenesis in the absence of cyclin D2

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Ansorg Anne

2012-05-01

Full Text Available Abstract Background Adult neurogenesis continuously adds new neurons to the dentate gyrus and the olfactory bulb. It involves the proliferation and subsequent differentiation of neuronal progenitors, and is thus closely linked to the cell cycle machinery. Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins. Among them, D-type cyclins control the exit from the G1 phase of the cell cycle. Cyclin D2 (cD2 has been shown to be required for the generation of new neurons in the neurogenic niches of the adult brain. It is differentially expressed during hippocampal development, and adult cD2 knock out (cD2KO mice virtually lack neurogenesis in the dentate gyrus and olfactory bulb. In the present study we examined the dynamics of postnatal and adult neurogenesis in the dentate gyrus (DG of cD2KO mice. Animals were injected with bromodeoxyuridine at seven time points during the first 10 months of life and brains were immunohistochemically analyzed for their potential to generate new neurons. Results Compared to their WT litters, cD2KO mice had considerably reduced numbers of newly born granule cells during the postnatal period, with neurogenesis becoming virtually absent around postnatal day 28. This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death. CD2KO mice did not show any of the age-related changes in neurogenesis and granule cell numbers that were seen in WT litters. Conclusions The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development. In cD2KO mice, hippocampal neurogenesis ceases at a time point at which the tertiary germinative matrix stops proliferating, indicating that cD2 becomes an essential requirement for ongoing neurogenesis with the transition from developmental to adult neurogenesis. Our data further support the notion that

Acupuncture for neurogenesis in experimental ischemic stroke: a systematic review and meta-analysis.

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Lu, Lin; Zhang, Xiao-guang; Zhong, Linda L D; Chen, Zi-xian; Li, Yan; Zheng, Guo-qing; Bian, Zhao-xiang

2016-01-20

Acupuncture has been used for patients with stroke and post-stroke rehabilitation for thousands of years. Previous studies reported that acupuncture enhanced stroke recovery through neurogenesis. Hence, we conducted a systematic review and meta-analysis for preclinical studies to assess the current evidence for acupuncture effect on neurogenesis in treating ischaemic stroke. Studies were obtained from six databases, including PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, VIP information database, and Chinese Biomedical Literature Database, Ultimately, 34 studies containing 1617 animals were identified. Neurogenesis markers of Brdu, Nestin, PSA-NCAM, NeuN and GFAP were selected as major outcomes. The pooled results of 15 studies marked with Brdu showed significant effects of acupuncture for improving proliferation when compared with control groups (P acupuncture for increasing proliferation when compared with control groups (P acupuncture for enhancing migration when compared with control groups (P acupuncture for stimulating differentiation when compared with control groups (P acupuncture is a prospective therapy targeting neurogenesis for ischemic stroke.

Hard-Diet Feeding Recovers Neurogenesis in the Subventricular Zone and Olfactory Functions of Mice Impaired by Soft-Diet Feeding

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Utsugi, Chizuru; Miyazono, Sadaharu; Osada, Kazumi; Sasajima, Hitoshi; Noguchi, Tomohiro; Matsuda, Mitsuyoshi; Kashiwayanagi, Makoto

2014-01-01

The subventricular zone (SVZ) generates an immense number of neurons even during adulthood. These neurons migrate to the olfactory bulb (OB) and differentiate into granule cells and periglomerular cells. The information broadcast by general odorants is received by the olfactory sensory neurons and transmitted to the OB. Recent studies have shown that a reduction of mastication impairs both neurogenesis in the hippocampus and brain functions. To examine these effects, we first measured the difference in Fos-immunoreactivity (Fos-ir) at the principal sensory trigeminal nucleus (Pr5), which receives intraoral touch information via the trigeminal nerve, when female adult mice ingested a hard or soft diet to explore whether soft-diet feeding could mimic impaired mastication. Ingestion of a hard diet induced greater expression of Fos-ir cells at the Pr5 than did a soft diet or no diet. Bromodeoxyuridine-immunoreactive (BrdU-ir) structures in sagittal sections of the SVZ and in the OB of mice fed a soft or hard diet were studied to explore the effects of changes in mastication on newly generated neurons. After 1 month, the density of BrdU-ir cells in the SVZ and OB was lower in the soft-diet-fed mice than in the hard-diet-fed mice. The odor preferences of individual female mice to butyric acid were tested in a Y-maze apparatus. Avoidance of butyric acid was reduced by the soft-diet feeding. We then explored the effects of the hard-diet feeding on olfactory functions and neurogenesis in the SVZ of mice impaired by soft-diet feeding. At 3 months of hard-diet feeding, avoidance of butyric acid was reversed and responses to odors and neurogenesis were recovered in the SVZ. The present results suggest that feeding with a hard diet improves neurogenesis in the SVZ, which in turn enhances olfactory function at the OB. PMID:24817277

A Common Language: How Neuroimmunological Cross Talk Regulates Adult Hippocampal Neurogenesis

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Odette Leiter

2016-01-01

Full Text Available Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus—a region crucial for learning and memory.

Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

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Lapanowski Karen

2010-02-01

Full Text Available Abstract Background Sublethal doses of whole brain irradiation (WBI are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE inhibitor, ramipril, as a mitigator of radiation injury in this context. Methods Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks. Results Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats. Conclusions Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory

Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin

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Eisch Amelia

2010-01-01

Full Text Available Abstract Background Survivin is a unique member of the inhibitor of apoptosis protein (IAP family in that it exhibits antiapoptotic properties and also promotes the cell cycle and mediates mitosis as a chromosome passenger protein. Survivin is highly expressed in neural precursor cells in the brain, yet its function there has not been elucidated. Results To examine the role of neural precursor cell survivin, we first showed that survivin is normally expressed in periventricular neurogenic regions in the embryo, becoming restricted postnatally to proliferating and migrating NPCs in the key neurogenic sites, the subventricular zone (SVZ and the subgranular zone (SGZ. We then used a conditional gene inactivation strategy to delete the survivin gene prenatally in those neurogenic regions. Lack of embryonic NPC survivin results in viable, fertile mice (SurvivinCamcre with reduced numbers of SVZ NPCs, absent rostral migratory stream, and olfactory bulb hypoplasia. The phenotype can be partially rescued, as intracerebroventricular gene delivery of survivin during embryonic development increases olfactory bulb neurogenesis, detected postnatally. SurvivinCamcre brains have fewer cortical inhibitory interneurons, contributing to enhanced sensitivity to seizures, and profound deficits in memory and learning. Conclusions The findings highlight the critical role that survivin plays during neural development, deficiencies of which dramatically impact on postnatal neural function.

Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

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Clara Penas

2015-04-01

Full Text Available Although casein kinase 1δ (CK1δ is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1 ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

Elevated homocysteine by levodopa is detrimental to neurogenesis in parkinsonian model.

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Jin Young Shin

Full Text Available BACKGROUND: Modulation of neurogenesis that acts as an endogenous repair mechanism would have a significant impact on future therapeutic strategies for Parkinson's disease (PD. Several studies demonstrated dopaminergic modulation of neurogenesis in the subventricular zone (SVZ of the adult brain. Levodopa, the gold standard therapy for PD, causes an increase in homocysteine levels that induces neuronal death via N-methyl-D-aspartate (NMDA receptor. The present study investigated whether elevated homocysteine by levodopa treatment in a parkinsonian model would modulate neurogenesis via NMDA receptor signal cascade and compared the effect of levodopa and pramipexol (PPX on neurogenic activity. METHODOLOGY/PRINCIPAL FINDINGS: Neurogenesis was assessed in vitro using neural progenitor cells (NPCs isolated from the SVZ and in vivo with the BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Modulation of homocysteine levels was evaluated using co-cultures of NPCs and astrocytes and PD animals. Immunochemical and Western blot analyses were used to measure neurogenesis and determine the cell death signaling. Levodopa treatment increased release of homocysteine on astrocytes culture media as well as in plasma and brain of PD animals. Increased homocysteine by levodopa led to increased apoptosis of NPCs through the NMDA receptor-dependent the extracellular signal-regulated kinase (ERK signaling pathways. The administration of a NMDA antagonist significantly attenuated apoptotic cell death in levodopa-treated NPCs and markedly increased the number of BrdU-positive cells in the SVZ of levodopa-treated PD animals. Comparative analysis revealed that PPX treatment significantly increased the number of NPCs and BrdU-positive cells in the SVZ of PD animals compared to levodopa treatment. Our present study demonstrated that increased homocysteine by levodopa has a detrimental effect on neurogenesis through NMDA receptor

The Circadian Molecular Clock Regulates Adult Hippocampal Neurogenesis by Controlling the Timing of Cell-Cycle Entry and Exit

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Pascale Bouchard-Cannon

2013-11-01

Full Text Available The subgranular zone (SGZ of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis.

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von Rüden, E-L; Avemary, J; Zellinger, C; Algermissen, D; Bock, P; Beineke, A; Baumgärtner, W; Stein, V M; Tipold, A; Potschka, H

2012-08-01

Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and

Impact of glucocorticoid on neurogenesis

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Haruki Odaka

2017-01-01

Full Text Available Neurogenesis is currently an area of great interest in neuroscience. It is closely linked to brain diseases, including mental disorders and neurodevelopmental disease. Both embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of stressors. Moreover, proliferation/differentiation of the neural stem/progenitor cells (NSPCs is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K/Akt, hedgehog, and Wnt. Our review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms; this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases.

APC/C-Cdh1 coordinates neurogenesis and cortical size during development

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Delgado-Esteban, Maria; García-Higuera, Irene; Maestre, Carolina; Moreno, Sergio; Almeida, Angeles

2013-12-01

The morphology of the adult brain is the result of a delicate balance between neural progenitor proliferation and the initiation of neurogenesis in the embryonic period. Here we assessed whether the anaphase-promoting complex/cyclosome (APC/C) cofactor, Cdh1—which regulates mitosis exit and G1-phase length in dividing cells—regulates neurogenesis in vivo. We use an embryo-restricted Cdh1 knockout mouse model and show that functional APC/C-Cdh1 ubiquitin ligase activity is required for both terminal differentiation of cortical neurons in vitro and neurogenesis in vivo. Further, genetic ablation of Cdh1 impairs the ability of APC/C to promote neurogenesis by delaying the exit of the progenitor cells from the cell cycle. This causes replicative stress and p53-mediated apoptotic death resulting in decreased number of cortical neurons and cortex size. These results demonstrate that APC/C-Cdh1 coordinates cortical neurogenesis and size, thus posing Cdh1 in the molecular pathogenesis of congenital neurodevelopmental disorders, such as microcephaly.

Of Mice and Men: Neurogenesis, Cognition and Alzheimer’s disease

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Orly eLazarov

2013-08-01

Full Text Available Neural stem cells are maintained in the subgranular layer of the dentate gyrus and in the subventricular zone in the adult mammalian brain throughout life. Neurogenesis is continuous, but its extent is tightly regulated by environmental factors, behavior, hormonal state, age and brain health. Increasing evidence supports a role for new neurons in cognitive function in rodents. Recent evidence delineates potential significant differences between adult neurogenesis in rodents and humans. Being context-dependent, neurogenesis in the human brain might be manifested differently than in the rodent brain. Decline in neurogenesis may play a role in cognitive deterioration, leading to the development of progressive learning and memory disorders, such as Alzheimer’s disease. This review discusses the different observations concerning neurogenesis in the rodent and human brain, and their functional implications for the healthy and diseased brain.

Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice

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Klaus Fabel

2009-11-01

Full Text Available Voluntary physical exercise (wheel running, RUN and environmental enrichment (ENR both stimulate adult hippocampal neurogenesis but do so by different mechanisms. RUN induces precursor cell proliferation, whereas ENR exerts a survival-promoting effect on newborn cells. In addition, continued RUN prevented the physiologically occurring age-related decline in precursor cell in the dentate gyrus but did not lead to a corresponding increase in net neurogenesis. We hypothesized that in the absence of appropriate cognitive stimuli the potential for neurogenesis could not be realized but that an increased potential by proliferating precursor cells due to RUN could actually lead to more adult neurogenesis if an appropriate survival-promoting stimulus follows the exercise. We thus asked whether a sequential combination of RUN and ENR (RUNENR would show additive effects that are distinct from the application of either paradigm alone. We found that the effects of 10 days of RUN followed by 35 days of ENR were additive in that the combined stimulation yielded an approximately 30% greater increase in new neurons than either stimulus alone, which also increased neurogenesis. Surprisingly, this result indicates that although overall the amount of proliferating cells in the dentate gyrus is poorly predictive of net adult neurogenesis, an increased neurogenic potential nevertheless provides the basis for a greater efficiency of the same survival-promoting stimulus. We thus propose that physical activity can “prime” the neurogenic region of the dentate gyrus for increased neurogenesis in the case the animal is exposed to an additional cognitive stimulus, here represented by the enrichment paradigm.

Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats

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Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto

2015-01-01

Highlights: • Maternal AFB 1 exposure effect on hippocampal neurogenesis was examined in rats. • AFB 1 reversibly reduced cell proliferation and type-3 progenitor cells in the SGZ. • Suppressed cholinergic signals to GABAergic interneurons may reduce type-3 cells. • Suppressed BDNF–TRKB signaling may contribute to aberration of neurogenesis. • The NOAEL for offspring was determined to be 0.1 ppm (7.1–13.6 μg/kg BW/day). - Abstract: To elucidate the maternal exposure effects of aflatoxin B 1 (AFB 1 ) and its metabolite aflatoxin M 1 , which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB 1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB 1 exposure. Following exposure to 1.0 ppm AFB 1 , offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin + progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥0.3 ppm, although T-box brain 2 + cells, tubulin beta III + cells, gamma-H2A histone family, member X + cells, and cyclin-dependent kinase inhibitor 1A + cells did not fluctuate in number. AFB 1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB 1 exposure reversibly affects hippocampal

EMMPRIN overexpression in SVZ neural progenitor cells increases their migration towards ischemic cortex.

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Kanemitsu, Michiko; Tsupykov, Oleg; Potter, Gaël; Boitard, Michael; Salmon, Patrick; Zgraggen, Eloisa; Gascon, Eduardo; Skibo, Galina; Dayer, Alexandre G; Kiss, Jozsef Z

2017-11-01

Stimulation of endogenous neurogenesis and recruitment of neural progenitors from the subventricular zone (SVZ) neurogenic site may represent a useful strategy to improve regeneration in the ischemic cortex. Here, we tested whether transgenic overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), the regulator of matrix metalloproteinases (MMPs) expression, in endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ) could increase migration towards ischemic injury. For this purpose, we applied a lentivector-mediated gene transfer system. We found that EMMPRIN-transduced progenitors exhibited enhanced MMP-2 activity in vitro and showed improved motility in 3D collagen gel as well as in cortical slices. Using a rat model of neonatal ischemia, we showed that EMMPRIN overexpressing SVZ cells invade the injured cortical tissue more efficiently than controls. Our results suggest that EMMPRIN overexpression could be suitable approach to improve capacities of endogenous or transplanted progenitors to invade the injured cortex. Copyright © 2017 Elsevier Inc. All rights reserved.

Progranulin regulates neurogenesis in the developing vertebrate retina.

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Walsh, Caroline E; Hitchcock, Peter F

2017-09-01

We evaluated the expression and function of the microglia-specific growth factor, Progranulin-a (Pgrn-a) during developmental neurogenesis in the embryonic retina of zebrafish. At 24 hpf pgrn-a is expressed throughout the forebrain, but by 48 hpf pgrn-a is exclusively expressed by microglia and/or microglial precursors within the brain and retina. Knockdown of Pgrn-a does not alter the onset of neurogenic programs or increase cell death, however, in its absence, neurogenesis is significantly delayed-retinal progenitors fail to exit the cell cycle at the appropriate developmental time and postmitotic cells do not acquire markers of terminal differentiation, and microglial precursors do not colonize the retina. Given the link between Progranulin and cell cycle regulation in peripheral tissues and transformed cells, we analyzed cell cycle kinetics among retinal progenitors following Pgrn-a knockdown. Depleting Pgrn-a results in a significant lengthening of the cell cycle. These data suggest that Pgrn-a plays a dual role during nervous system development by governing the rate at which progenitors progress through the cell cycle and attracting microglial progenitors into the embryonic brain and retina. Collectively, these data show that Pgrn-a governs neurogenesis by regulating cell cycle kinetics and the transition from proliferation to cell cycle exit and differentiation. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 77: 1114-1129, 2017. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc.

Effect of calcitonin gene-related peptide on the neurogenesis of rat adipose-derived stem cells in vitro.

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Qin Yang

Full Text Available Calcitonin gene-related peptide (CGRP promotes neuron recruitment and neurogenic activity. However, no evidence suggests that CGRP affects the ability of stem cells to differentiate toward neurogenesis. In this study, we genetically modified rat adipose-derived stem cells (ADSCs with the CGRP gene (CGRP-ADSCs and subsequently cultured in complete neural-induced medium. The formation of neurospheres, cellular morphology, and proliferative capacity of ADSCs were observed. In addition, the expression of the anti-apoptotic protein Bcl-2 and special markers of neural cells, such as Nestin, MAP2, RIP and GFAP, were evaluated using Western blot and immunocytochemistry analysis. The CGRP-ADSCs displayed a greater proliferation than un-transduced (ADSCs and Vector-transduced (Vector-ADSCs ADSCs (p<0.05, and lower rates of apoptosis, associated with the incremental expression of Bcl-2, were also observed for CGRP-ADSCs. Moreover, upon neural induction, CGRP-ADSCs formed markedly more and larger neurospheres and showed round cell bodies with more branching extensions contacted with neighboring cells widely. Furthermore, the expression levels of Nestin, MAP2, and RIP in CGRP-ADSCs were markedly increased, resulting in higher levels than the other groups (p<0.05; however, GFAP was distinctly undetectable until day 7, when slight GFAP expression was detected among all groups. Wnt signals, primarily Wnt 3a, Wnt 5a and β-catenin, regulate the neural differentiation of ADSCs, and CGRP gene expression apparently depends on canonical Wnt signals to promote the neurogenesis of ADSCs. Consequently, ADSCs genetically modified with CGRP exhibit stronger potential for differentiation and neurogenesis in vitro, potentially reflecting the usefulness of ADSCs as seed cells in therapeutic strategies for spinal cord injury.

Taxonomic separation of hippocampal networks: principal cell populations and adult neurogenesis

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Roelof Maarten evan Dijk

2016-03-01

Full Text Available While many differences in hippocampal anatomy have been described between species, it is typically not clear if they are specific to a particular species and related to functional requirements or if they are shared by species of larger taxonomic units. Without such information, it is difficult to infer how anatomical differences may impact on hippocampal function, because multiple taxonomic levels need to be considered to associate behavioral and anatomical changes. To provide information on anatomical changes within and across taxonomic ranks, we present a quantitative assessment of hippocampal principal cell populations in 20 species or strain groups, with emphasis on rodents, the taxonomic group that provides most animals used in laboratory research. Of special interest is the importance of adult hippocampal neurogenesis in species-specific adaptations relative to other cell populations. Correspondence analysis of cell numbers shows that across taxonomic units, phylogenetically related species cluster together, sharing similar proportions of principal cell populations. CA3 and hilus are strong separators that place rodent species into a tight cluster based on their relatively large CA3 and small hilus while non-rodent species (including humans and non-human primates are placed on the opposite side of the spectrum. Hilus and CA3 are also separators within rodents, with a very large CA3 and rather small hilar cell populations separating mole-rats from other rodents that, in turn, are separated from each other by smaller changes in the proportions of CA1 and granule cells. When adult neurogenesis is included, the relatively small populations of young neurons, proliferating cells and hilar neurons become main drivers of taxonomic separation within rodents. The observations provide challenges to the computational modeling of hippocampal function, suggest differences in the organization of hippocampal information streams in rodent and non

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions

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Ming, Guo-li; Song, Hongjun

2011-01-01

Summary Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade. PMID:21609825

IGF-I: A key growth factor that regulates neurogenesis and synaptogenesis from embryonic to adult stages of the brain

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Vanesa eNieto-Estévez

2016-02-01

Full Text Available The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs. This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP and the subventricular zone-olfactory bulb (SVZ-OB. By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also, by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis and neuron integration in synaptic circuits.

IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

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Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

2016-01-01

The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.

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Bouchard-Cannon, Pascale; Mendoza-Viveros, Lucia; Yuen, Andrew; Kærn, Mads; Cheng, Hai-Ying M

2013-11-27

The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior.

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Sun, Dong; Sun, Xiang-Dong; Zhao, Lu; Lee, Dae-Hoon; Hu, Jin-Xia; Tang, Fu-Lei; Pan, Jin-Xiu; Mei, Lin; Zhu, Xiao-Juan; Xiong, Wen-Cheng

2018-01-08

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention.

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Kim, Ah Hyun; Chun, Hye Jeong; Lee, Seulah; Kim, Hyung Sik; Lee, Jaewon

2017-08-01

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose-dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits. Copyright © 2017 Elsevier Ltd. All rights reserved.

Abrogation of Early Apoptosis Does Not Alter Late Inhibition of Hippocampal Neurogenesis After Irradiation

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Li Yuqing; Aubert, Isabelle; Wong, C. Shun

2010-01-01

Purpose: Irradiation of the adult brain results in acute apoptosis of neural progenitors and vascular endothelial cells, as well as late dysfunction of neural progenitors and inhibition of neurogenesis. We sought to determine whether the early apoptotic response has a causative role in late inhibition of neurogenesis after cranial irradiation. Methods and Materials: Using a genetic approach with p53 and smpd1 transgenic mice and a pharmacologic approach with basic fibroblast growth factor (bFGF) to abrogate the early apoptotic response, we evaluated the late inhibition of neurogenesis in the hippocampal dentate gyrus after cranial irradiation. Results: In dentate gyrus, subgranular neural progenitors underwent p53-dependent apoptosis within 24 h after irradiation. Despite a near abrogation of neural progenitor apoptosis in p53-/- mice, the reduction in newborn neurons in dentate gyrus at 9 weeks after irradiation in p53-/- mice was not different from that observed in wildtype controls. Endothelial cell apoptosis after radiation is mediated by membrane damage initiated by activation of acid sphingomyelinase (ASMase). Deletion of the smpd1 gene (which encodes ASMase) attenuated the apoptotic response of endothelial cells. At 9 weeks after irradiation, the inhibition of hippocampal neurogenesis was not rescued by ASMase deficiency. Intravenous administration of bFGF protected both endothelial cells and neural progenitors against radiation-induced apoptosis. There was no protection against inhibition of neurogenesis at 9 weeks after irradiation in bFGF-treated mice. Conclusion: Early apoptotic death of neural progenitors, endothelial cells, or both does not have a causative association with late inhibition of neurogenesis after irradiation.

Retinoic acid-treated pluripotent stem cells undergoing neurogenesis present increased aneuploidy and micronuclei formation.

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Rafaela C Sartore

Full Text Available The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC cells, embryonic stem (ES cells and induced pluripotent stem (iPS cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2-fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naïve cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal

Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory.

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Hung, Hui-Chi; Hsiao, Ya-Hsin; Gean, Po-Wu

2015-10-01

It is now recognized that neurogenesis occurs throughout life predominantly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. In the present study, we investigated the relationship between neurogenesis in the amygdala and extinction of fear memory. Mice received 15 tone-footshock pairings. Twenty-four hours after training, the mice were given 15 tone-alone trials (extinction training) once per day for 7 days. Two hours before extinction training, the mice were injected intraperitoneally with 5-bromo-3-deoxyuridine (BrdU). BrdU-positive and NeuN-positive cells were analyzed 52 days after the training. A group of mice that received tone-footshock pairings but no extinction training served as controls (FC+No-Ext). The number of BrdU(+)/NeuN(+) cells was significantly higher in the extinction (FC+Ext) than in the FC+No-Ext mice. Proliferation inhibitor methylazoxymethanol acetate (MAM) or DNA synthesis inhibitor cytosine arabinoside (Ara-C) reduced neurogenesis and retarded extinction. Silencing Sonic hedgehog (Shh) gene with short hairpin interfering RNA (shRNA) by means of a retrovirus expression system to knockdown Shh specifically in the mitotic neurons reduced neurogenesis and retarded extinction. By contrast, over-expression of Shh increased neurogenesis and facilitated extinction. These results suggest that amygdala neurogenesis and Shh signaling are involved in the extinction of fear memory. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Enhanced Dentate Neurogenesis after Brain Injury Undermines Long-Term Neurogenic Potential and Promotes Seizure Susceptibility

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Eric J. Neuberger

2017-09-01

Full Text Available Hippocampal dentate gyrus is a focus of enhanced neurogenesis and excitability after traumatic brain injury. Increased neurogenesis has been proposed to aid repair of the injured network. Our data show that an early increase in neurogenesis after fluid percussion concussive brain injury is transient and is followed by a persistent decrease compared with age-matched controls. Post-injury changes in neurogenesis paralleled changes in neural precursor cell proliferation and resulted in a long-term decline in neurogenic capacity. Targeted pharmacology to restore post-injury neurogenesis to control levels reversed the long-term decline in neurogenic capacity. Limiting post-injury neurogenesis reduced early increases in dentate excitability and seizure susceptibility. Our results challenge the assumption that increased neurogenesis after brain injury is beneficial and show that early post-traumatic increases in neurogenesis adversely affect long-term outcomes by exhausting neurogenic potential and enhancing epileptogenesis. Treatments aimed at limiting excessive neurogenesis can potentially restore neuroproliferative capacity and limit epilepsy after brain injury.

Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice.

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Anna Fiorentini

Full Text Available BACKGROUND: Alzheimer's disease (AD is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. METHODOLOGY/PRINCIPAL FINDINGS: The double transgenic (Tg CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3β and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium's ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Aβ deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.

Collective cell migration during inflammatory response

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Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

2012-02-01

Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

Neurogenesis-mediated forgetting minimizes proactive interference.

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Epp, Jonathan R; Silva Mera, Rudy; Köhler, Stefan; Josselyn, Sheena A; Frankland, Paul W

2016-02-26

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting.

L-carnitine contributes to enhancement of neurogenesis from mesenchymal stem cells through Wnt/β-catenin and PKA pathway.

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Fathi, Ezzatollah; Farahzadi, Raheleh; Charoudeh, Hojjatollah Nozad

2017-03-01

The identification of factors capable of enhancing neurogenesis has great potential for cellular therapies in neurodegenerative diseases. Multiple studies have shown the neuroprotective effects of L-carnitine (LC). This study determined whether neuronal differentiation of rat adipose tissue-derived mesenchymal stem cells (ADSCs) can be activated by LC. In this study, protein kinase A (PKA) and Wnt/β-catenin pathways were detected to show if this activation was due to these pathways. The expression of LC-induced neurogenesis markers in ADSCs was characterized using real-time PCR. ELISA was conducted to assess the expression of cyclic adenosine monophosphate (cAMP) and PKA. The expression of β-catenin, reduced dickkopf1 (DKK1), low-density lipoprotein receptor-related protein 5 (LRP5), Wnt1, and Wnt3a genes as Wnt/β-catenin signaling members were used to detect the Wnt/β-catenin pathway. It was observed that LC could promote neurogenesis in ADSCs as well as expression of some neurogenic markers. Moreover, LC causes to increase the cAMP levels and PKA activity. Treatment of ADSCs with H-89 (dihydrochloride hydrate) as PKA inhibitor significantly inhibited the promotion of neurogenic markers, indicating that the PKA signaling pathway could be involved in neurogenesis induction. Analyses of real-time PCR data showed that the mRNA expressions of β-catenin, DKK1, LRP5c-myc, Wnt1, and Wnt3a were increased in the presence of LC. Therefore, the present study showed that LC promotes ADSCs neurogenesis and the LC-induced neurogenic markers could be due to both the PKA and Wnt/β-catenin signaling pathway. Impact statement Neural tissue has long been believed as incapable of regeneration and the identification of cell types and factors capable of neuronal differentiation has generated intense interest. Mesenchymal stem cells (MSCs) are considered as potential targets for stem cell-based therapy. L-carnitin (LC) as an antioxidant may have neuroprotective effects in

Physical Exercise Leads to Rapid Adaptations in Hippocampal Vasculature : Temporal Dynamics and Relationship to Cell Proliferation and Neurogenesis

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Van der Borght, Karin; Kobor-Nyakas, Dora E.; Klauke, Karin; Eggen, Bart J. L.; Nyakas, Csaba; Van der Zee, Eddy A.; Meerlo, Peter

2009-01-01

Increased levels of angiogenesis and neurogenesis possibly mediate the beneficial effects of physical activity on hippocampal plasticity. This study was designed to investigate the temporal dynamics of exercise-induced changes in hippocampal angiogenesis and cell proliferation. Mice were housed with

Effects of amphetamine administration on neurogenesis in adult rats

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Tomasz Stępień

2017-12-01

Full Text Available In our study expression of phospho-(Ser-10-histone H3 (pH3S10, a marker for the early stage of neurogenesis, and cellular early response genes were investigated using c-Fos protein as an example of a transcription factor in the neurogenic process in rats. Neurogenesis in the adult brain is regulated by endo- and exogenous factors, which influence the proliferation potential of progenitor cells and accelerate the dendritic development of newborn neurons. D-amphetamine, a psychoactive substance, is one of the exogenous factors able to influence the process of neurogenesis. The rats were injected with D-amphetamine at a dose of 1.5 mg/kg/body weight (b.w. under one administration scheme. Analysis of the pH3S10 and c-Fos expression levels in the group of D-amphetamine administered rats provided evidence of enhanced expression of these proteins in the regions of neurogenesis occurrence in rats. However, conclusions concerning stimulant effects of amphetamine on neurogenesis should be formulated with great caution, taking into account amphetamine dosage and the administration scheme. It should also be remembered that doses of psychoactive substances used in animal models can be lethal to humans.

Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell-autonomous fashion.

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Völkening, Bianca; Schönig, Kai; Kronenberg, Golo; Bartsch, Dusan; Weber, Tillmann

2017-05-01

Ca 2+ is a universal signal transducer which fulfills essential functions in cell development and differentiation. CACNA1C, the gene encoding the alpha-1C subunit (i.e., Ca v 1.2) of the voltage-dependent l-type calcium channel (LTCC), has been implicated as a risk gene in a variety of neuropsychiatric disorders. To parse the role of Ca v 1.2 channels located on astrocyte-like stem cells and their descendants in the development of new granule neurons, we created Tg GLAST-CreERT2 /Cacna1c fl/fl /RCE:loxP mice, a transgenic tool that allows cell-type-specific inducible deletion of Cacna1c. The EGFP reporter was used to trace the progeny of recombined type-1 cells. FACS-sorted Cacna1c-deficient neural precursor cells from the dentate gyrus showed reduced proliferative activity in neurosphere cultures. Moreover, under differentiation conditions, Cacna1c-deficient NPCs gave rise to fewer neurons and more astroglia. Similarly, under basal conditions in vivo, Cacna1c gene deletion in type-1 cells decreased type-1 cell proliferation and reduced the neuronal fate-choice decision of newly born cells, resulting in reduced net hippocampal neurogenesis. Unexpectedly, electroconvulsive seizures completely compensated for the proliferation deficit of Cacna1c deficient type-1 cells, indicating that there must be Ca v 1.2-independent mechanisms of controlling proliferation related to excitation. In the aggregate, this is the first report demonstrating the presence of functional L-type 1.2 channels on type-1 cells. Ca v 1.2 channels promote type-1 cell proliferation and push the glia-to-neuron ratio in the direction of a neuronal fate choice and subsequent neuronal differentiation. Ca v 1.2 channels expressed on NPCs and their progeny possess the ability to shape neurogenesis in a cell-autonomous fashion. © 2017 Wiley Periodicals, Inc.

Multi-cellular logistics of collective cell migration.

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Masataka Yamao

Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

The Tlx gene regulates the timing of neurogenesis in the cortex.

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Roy, Kristine; Kuznicki, Kathleen; Wu, Qiang; Sun, Zhuoxin; Bock, Dagmar; Schutz, Gunther; Vranich, Nancy; Monaghan, A Paula

2004-09-22

The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx-/- embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.

Analysis of neural progenitors from embryogenesis to juvenile adult in Xenopus laevis reveals biphasic neurogenesis and continuous lengthening of the cell cycle

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Raphaël Thuret

2015-12-01

Full Text Available Xenopus laevis is a prominent model system for studying neural development, but our understanding of the long-term temporal dynamics of neurogenesis remains incomplete. Here, we present the first continuous description of neurogenesis in X. laevis, covering the entire period of development from the specification of neural ectoderm during gastrulation to juvenile frog. We have used molecular markers to identify progenitors and neurons, short-term bromodeoxyuridine (BrdU incorporation to map the generation of newborn neurons and dual pulse S-phase labelling to characterise changes in their cell cycle length. Our study revealed the persistence of Sox3-positive progenitor cells from the earliest stages of neural development through to the juvenile adult. Two periods of intense neuronal generation were observed, confirming the existence of primary and secondary waves of neurogenesis, punctuated by a period of quiescence before metamorphosis and culminating in another period of quiescence in the young adult. Analysis of multiple parameters indicates that neural progenitors alternate between global phases of differentiation and amplification and that, regardless of their behaviour, their cell cycle lengthens monotonically during development, at least at the population level.

Embryonic cell-cell adhesion: a key player in collective neural crest migration.

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Barriga, Elias H; Mayor, Roberto

2015-01-01

Cell migration is essential for morphogenesis, adult tissue remodeling, wound healing, and cancer cell migration. Cells can migrate as individuals or groups. When cells migrate in groups, cell-cell interactions are crucial in order to promote the coordinated behavior, essential for collective migration. Interestingly, recent evidence has shown that cell-cell interactions are also important for establishing and maintaining the directionality of these migratory events. We focus on neural crest cells, as they possess extraordinary migratory capabilities that allow them to migrate and colonize tissues all over the embryo. Neural crest cells undergo an epithelial-to-mesenchymal transition at the same time than perform directional collective migration. Cell-cell adhesion has been shown to be an important source of planar cell polarity and cell coordination during collective movement. We also review molecular mechanisms underlying cadherin turnover, showing how the modulation and dynamics of cell-cell adhesions are crucial in order to maintain tissue integrity and collective migration in vivo. We conclude that cell-cell adhesion during embryo development cannot be considered as simple passive resistance to force, but rather participates in signaling events that determine important cell behaviors required for cell migration. © 2015 Elsevier Inc. All rights reserved.

Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis

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Müller Anke

2010-06-01

Full Text Available Abstract Background Adult neurogenesis is a particular example of brain plasticity that is partially modulated by the endocannabinoid system. Whereas the impact of synthetic cannabinoids on the neuronal progenitor cells has been described, there has been lack of information about the action of plant-derived extracts on neurogenesis. Therefore we here focused on the effects of Δ9-tetrahydrocannabinol (THC and Cannabidiol (CBD fed to female C57Bl/6 and Nestin-GFP-reporter mice on proliferation and maturation of neuronal progenitor cells and spatial learning performance. In addition we used cannabinoid receptor 1 (CB1 deficient mice and treatment with CB1 antagonist AM251 in Nestin-GFP-reporter mice to investigate the role of the CB1 receptor in adult neurogenesis in detail. Results THC and CBD differed in their effects on spatial learning and adult neurogenesis. CBD did not impair learning but increased adult neurogenesis, whereas THC reduced learning without affecting adult neurogenesis. We found the neurogenic effect of CBD to be dependent on the CB1 receptor, which is expressed over the whole dentate gyrus. Similarly, the neurogenic effect of environmental enrichment and voluntary wheel running depends on the presence of the CB1 receptor. We found that in the absence of CB1 receptors, cell proliferation was increased and neuronal differentiation reduced, which could be related to CB1 receptor mediated signaling in Doublecortin (DCX-expressing intermediate progenitor cells. Conclusion CB1 affected the stages of adult neurogenesis that involve intermediate highly proliferative progenitor cells and the survival and maturation of new neurons. The pro-neurogenic effects of CBD might explain some of the positive therapeutic features of CBD-based compounds.

A weak magnetic field inhibits hippocampal neurogenesis in SD rats

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Zhang, B.; Tian, L.; Cai, Y.; Pan, Y.

2017-12-01

Geomagnetic field is an important barrier that protects life forms on Earth from solar wind and radiation. Paleomagnetic data have well demonstrated that the strength of ancient geomagnetic field was dramatically weakened during a polarity transition. Accumulating evidence has shown that weak magnetic field exposures has serious adverse effects on the metabolism and behaviors in organisms. Hippocampal neurogenesis occurs throughout life in mammals' brains which plays a key role in brain function, and can be influenced by animals' age as well as environmental factors, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we have investigated the weak magnetic field effects on hippocampal neurogenesis of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, a weak magnetic field (≤1.3 μT) and the geomagnetic fields (51 μT).The latter is treated as a control condition. SD rats were exposure to the weak magnetic field up to 6 weeks. We measured the changes of newborn nerve cells' proliferation and survival, immature neurons, neurons and apoptosis in the dentate gyrus (DG) of hippocampus in SD rats. Results showed that, the weak magnetic field (≤1.3 μT) inhibited their neural stem cells proliferation and significantly reduced the survival of newborn nerve cells, immature neurons and neurons after 2 or 4 weeks continuous treatment (i.e. exposure to weak magnetic field). Moreover, apoptosis tests indicated the weak magnetic field can promote apoptosis of nerve cells in the hippocampus after 4 weeks treatment. Together, our new data indicate that weak magnetic field decrease adult hippocampal neurogenesis through inhibiting neural stem cells proliferation and promoting apoptosis, which provides useful experimental constraints on better understanding the mechanism of linkage between life and geomagnetic field.

Mammalian neurogenesis requires Treacle-Plk1 for precise control of spindle orientation, mitotic progression, and maintenance of neural progenitor cells.

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Daisuke Sakai

Full Text Available The cerebral cortex is a specialized region of the brain that processes cognitive, motor, somatosensory, auditory, and visual functions. Its characteristic architecture and size is dependent upon the number of neurons generated during embryogenesis and has been postulated to be governed by symmetric versus asymmetric cell divisions, which mediate the balance between progenitor cell maintenance and neuron differentiation, respectively. The mechanistic importance of spindle orientation remains controversial, hence there is considerable interest in understanding how neural progenitor cell mitosis is controlled during neurogenesis. We discovered that Treacle, which is encoded by the Tcof1 gene, is a novel centrosome- and kinetochore-associated protein that is critical for spindle fidelity and mitotic progression. Tcof1/Treacle loss-of-function disrupts spindle orientation and cell cycle progression, which perturbs the maintenance, proliferation, and localization of neural progenitors during cortical neurogenesis. Consistent with this, Tcof1(+/- mice exhibit reduced brain size as a consequence of defects in neural progenitor maintenance. We determined that Treacle elicits its effect via a direct interaction with Polo-like kinase1 (Plk1, and furthermore we discovered novel in vivo roles for Plk1 in governing mitotic progression and spindle orientation in the developing mammalian cortex. Increased asymmetric cell division, however, did not promote increased neuronal differentiation. Collectively our research has therefore identified Treacle and Plk1 as novel in vivo regulators of spindle fidelity, mitotic progression, and proliferation in the maintenance and localization of neural progenitor cells. Together, Treacle and Plk1 are critically required for proper cortical neurogenesis, which has important implications in the regulation of mammalian brain size and the pathogenesis of congenital neurodevelopmental disorders such as microcephaly.

Short-lived, transitory cell-cell interactions foster migration-dependent aggregation.

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Melissa D Pope

Full Text Available During embryonic development, motile cells aggregate into cohesive groups, which give rise to tissues and organs. The role of cell migration in regulating aggregation is unclear. The current paradigm for aggregation is based on an equilibrium model of differential cell adhesivity to neighboring cells versus the underlying substratum. In many biological contexts, however, dynamics is critical. Here, we provide evidence that multicellular aggregation dynamics involves both local adhesive interactions and transport by cell migration. Using time-lapse video microscopy, we quantified the duration of cell-cell contacts among migrating cells that collided and adhered to another cell. This lifetime of cell-cell interactions exhibited a monotonic decreasing dependence on substratum adhesivity. Parallel quantitative measurements of cell migration speed revealed that across the tested range of adhesive substrata, the mean time needed for cells to migrate and encounter another cell was greater than the mean adhesion lifetime, suggesting that aggregation dynamics may depend on cell motility instead of the local differential adhesivity of cells. Consistent with this hypothesis, aggregate size exhibited a biphasic dependence on substratum adhesivity, matching the trend we observed for cell migration speed. Our findings suggest a new role for cell motility, alongside differential adhesion, in regulating developmental aggregation events and motivate new design principles for tuning aggregation dynamics in tissue engineering applications.

Entropy measures of collective cell migration

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Whitby, Ariadne; Parrinello, Simona; Faisal, Aldo

2015-03-01

Collective cell migration is a critical process during tissue formation and repair. To this end there is a need to develop tools to quantitatively measure the dynamics of collective cell migration obtained from microscopy data. Drawing on statistical physics we use entropy of velocity fields derived from dense optic flow to quantitatively measure collective migration. Using peripheral nerve repair after injury as experimental system, we study how Schwann cells, guided by fibroblasts, migrate in cord-like structures across the cut, paving a highway for neurons. This process of emergence of organised behaviour is key for successful repair, yet the emergence of leader cells and transition from a random to ordered state is not understood. We find fibroblasts induce correlated directionality in migrating Schwann cells as measured by a decrease in the entropy of motion vector. We show our method is robust with respect to image resolution in time and space, giving a principled assessment of how various molecular mechanisms affect macroscopic features of collective cell migration. Finally, the generality of our method allows us to process both simulated cell movement and microscopic data, enabling principled fitting and comparison of in silico to in vitro. ICCS, Imperial College London & MRC Clinical Sciences Centre.

Neurogenesis in the aging brain.

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Apple, Deana M; Solano-Fonseca, Rene; Kokovay, Erzsebet

2017-10-01

Adult neurogenesis is the process of producing new neurons from neural stem cells (NSCs) for integration into the brain circuitry. Neurogenesis occurs throughout life in the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. However, during aging, NSCs and their progenitors exhibit reduced proliferation and neuron production, which is thought to contribute to age-related cognitive impairment and reduced plasticity that is necessary for some types of brain repair. In this review, we describe NSCs and their niches during tissue homeostasis and how they undergo age-associated remodeling and dysfunction. We also discuss some of the functional ramifications in the brain from NSC aging. Finally, we discuss some recent insights from interventions in NSC aging that could eventually translate into therapies for healthy brain aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

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Astha Malik

Full Text Available Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ. Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte

Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats

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Klein, Anders Bue; Flagstad, P; Kristjansen, P E G

2008-01-01

Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants.......Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants....

Lung cells support osteosarcoma cell migration and survival.

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Yu, Shibing; Fourman, Mitchell Stephen; Mahjoub, Adel; Mandell, Jonathan Brendan; Crasto, Jared Anthony; Greco, Nicholas Giuseppe; Weiss, Kurt Richard

2017-01-25

Osteosarcoma (OS) is the most common primary bone tumor, with a propensity to metastasize to the lungs. Five-year survival for metastatic OS is below 30%, and has not improved for several decades despite the introduction of multi-agent chemotherapy. Understanding OS cell migration to the lungs requires an evaluation of the lung microenvironment. Here we utilized an in vitro lung cell and OS cell co-culture model to explore the interactions between OS and lung cells, hypothesizing that lung cells would promote OS cell migration and survival. The impact of a novel anti-OS chemotherapy on OS migration and survival in the lung microenvironment was also examined. Three human OS cell lines (SJSA-1, Saos-2, U-2) and two human lung cell lines (HULEC-5a, MRC-5) were cultured according to American Type Culture Collection recommendations. Human lung cell lines were cultured in growth medium for 72 h to create conditioned media. OS proliferation was evaluated in lung co-culture and conditioned media microenvironment, with a murine fibroblast cell line (NIH-3 T3) in fresh growth medium as controls. Migration and invasion were measured using a real-time cell analysis system. Real-time PCR was utilized to probe for Aldehyde Dehydrogenase (ALDH1) expression. Osteosarcoma cells were also transduced with a lentivirus encoding for GFP to permit morphologic analysis with fluorescence microscopy. The anti-OS efficacy of Disulfiram, an ALDH-inhibitor previously shown to inhibit OS cell proliferation and metastasis in vitro, was evaluated in each microenvironment. Lung-cell conditioned medium promoted osteosarcoma cell migration, with a significantly higher attractive effect on all three osteosarcoma cell lines compared to basic growth medium, 10% serum containing medium, and NIH-3 T3 conditioned medium (p cell conditioned medium induced cell morphologic changes, as demonstrated with GFP-labeled cells. OS cells cultured in lung cell conditioned medium had increased alkaline

Multiscale Cues Drive Collective Cell Migration

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Nam, Ki-Hwan; Kim, Peter; Wood, David K.; Kwon, Sunghoon; Provenzano, Paolo P.; Kim, Deok-Ho

2016-07-01

To investigate complex biophysical relationships driving directed cell migration, we developed a biomimetic platform that allows perturbation of microscale geometric constraints with concomitant nanoscale contact guidance architectures. This permits us to elucidate the influence, and parse out the relative contribution, of multiscale features, and define how these physical inputs are jointly processed with oncogenic signaling. We demonstrate that collective cell migration is profoundly enhanced by the addition of contract guidance cues when not otherwise constrained. However, while nanoscale cues promoted migration in all cases, microscale directed migration cues are dominant as the geometric constraint narrows, a behavior that is well explained by stochastic diffusion anisotropy modeling. Further, oncogene activation (i.e. mutant PIK3CA) resulted in profoundly increased migration where extracellular multiscale directed migration cues and intrinsic signaling synergistically conspire to greatly outperform normal cells or any extracellular guidance cues in isolation.

Toll-like receptor 2 promotes neurogenesis from the dentate gyrus after photothrombotic cerebral ischemia in mice.

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Seong, Kyung-Joo; Kim, Hyeong-Jun; Cai, Bangrong; Kook, Min-Suk; Jung, Ji-Yeon; Kim, Won-Jae

2018-03-01

The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

Modelling collective cell migration of neural crest.

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Szabó, András; Mayor, Roberto

2016-10-01

Collective cell migration has emerged in the recent decade as an important phenomenon in cell and developmental biology and can be defined as the coordinated and cooperative movement of groups of cells. Most studies concentrate on tightly connected epithelial tissues, even though collective migration does not require a constant physical contact. Movement of mesenchymal cells is more independent, making their emergent collective behaviour less intuitive and therefore lending importance to computational modelling. Here we focus on such modelling efforts that aim to understand the collective migration of neural crest cells, a mesenchymal embryonic population that migrates large distances as a group during early vertebrate development. By comparing different models of neural crest migration, we emphasize the similarity and complementary nature of these approaches and suggest a future direction for the field. The principles derived from neural crest modelling could aid understanding the collective migration of other mesenchymal cell types. Copyright © 2016 Elsevier Ltd. All rights reserved.

Substrate Curvature Regulates Cell Migration -A Computational Study

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He, Xiuxiu; Jiang, Yi

Cell migration in host microenvironment is essential to cancer etiology, progression and metastasis. Cellular processes of adhesion, cytoskeletal polymerization, contraction, and matrix remodeling act in concert to regulate cell migration, while local extracellular matrix architecture modulate these processes. In this work we study how stromal microenvironment with native and cell-derived curvature at micron-meter scale regulate cell motility pattern. We developed a 3D model of single cell migration on a curved substrate. Mathematical analysis of cell morphological adaption to the cell-substrate interface shows that cell migration on convex surfaces deforms more than on concave surfaces. Both analytical and simulation results show that curved surfaces regulate the cell motile force for cell's protruding front through force balance with focal adhesion and cell contraction. We also found that cell migration on concave substrates is more persistent. These results offer a novel biomechanical explanation to substrate curvature regulation of cell migration. NIH 1U01CA143069.

Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

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Sanberg Paul R

2008-02-01

Full Text Available Abstract Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis.

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O'Léime, Ciarán S; Cryan, John F; Nolan, Yvonne M

2017-11-01

Hippocampal neurogenesis, the process by which new neurons are born and develop into the host circuitry, begins during embryonic development and persists throughout adulthood. Over the last decade considerable insights have been made into the role of hippocampal neurogenesis in cognitive function and the cellular mechanisms behind this process. Additionally, an increasing amount of evidence exists on the impact of environmental factors, such as stress and neuroinflammation on hippocampal neurogenesis and subsequent impairments in cognition. Elevated expression of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus is established as a significant contributor to the neuronal demise evident in many neurological and psychiatric disorders and is now known to negatively regulate hippocampal neurogenesis. In order to prevent the deleterious effects of IL-1β on neurogenesis it is necessary to identify signalling pathways and regulators of neurogenesis within neural progenitor cells that can interact with IL-1β. Nuclear receptors are ligand regulated transcription factors that are involved in modulating a large number of cellular processes including neurogenesis. In this review we focus on the signalling mechanisms of specific nuclear receptors involved in regulating neurogenesis (glucocorticoid receptors, peroxisome proliferator activated receptors, estrogen receptors, and nuclear receptor subfamily 2 group E member 1 (NR2E1 or TLX)). We propose that these nuclear receptors could be targeted to inhibit neuroinflammatory signalling pathways associated with IL-1β. We discuss their potential to be therapeutic targets for neuroinflammatory disorders affecting hippocampal neurogenesis and associated cognitive function. Copyright © 2017 Elsevier Inc. All rights reserved.

SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory.

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Chen, Qian; Kogan, Jeffrey H; Gross, Adam K; Zhou, Yuan; Walton, Noah M; Shin, Rick; Heusner, Carrie L; Miyake, Shinichi; Tajinda, Katsunori; Tamura, Kouichi; Matsumoto, Mitsuyuki

2012-09-01

SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (Tg, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 Tg mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 Tg mice. In a spatial pattern separation task, SREB2 Tg mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 Tg and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

From network structure to network reorganization: implications for adult neurogenesis

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Schneider-Mizell, Casey M; Zochowski, Michal R; Sander, Leonard M; Parent, Jack M; Ben-Jacob, Eshel

2010-01-01

Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells

The mammalian adult neurogenesis gene ontology (MANGO provides a structural framework for published information on genes regulating adult hippocampal neurogenesis.

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Rupert W Overall

Full Text Available BACKGROUND: Adult hippocampal neurogenesis is not a single phenotype, but consists of a number of sub-processes, each of which is under complex genetic control. Interpretation of gene expression studies using existing resources often does not lead to results that address the interrelatedness of these processes. Formal structure, such as provided by ontologies, is essential in any field for comprehensive interpretation of existing knowledge but, until now, such a structure has been lacking for adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We have created a resource with three components 1. A structured ontology describing the key stages in the development of adult hippocampal neural stem cells into functional granule cell neurons. 2. A comprehensive survey of the literature to annotate the results of all published reports on gene function in adult hippocampal neurogenesis (257 manuscripts covering 228 genes to the appropriate terms in our ontology. 3. An easy-to-use searchable interface to the resulting database made freely available online. The manuscript presents an overview of the database highlighting global trends such as the current bias towards research on early proliferative stages, and an example gene set enrichment analysis. A limitation of the resource is the current scope of the literature which, however, is growing by around 100 publications per year. With the ontology and database in place, new findings can be rapidly annotated and regular updates of the database will be made publicly available. CONCLUSIONS/SIGNIFICANCE: The resource we present allows relevant interpretation of gene expression screens in terms of defined stages of postnatal neuronal development. Annotation of genes by hand from the adult neurogenesis literature ensures the data are directly applicable to the system under study. We believe this approach could also serve as an example to other fields in a 'bottom-up' community effort complementing the already

A Customizable Chamber for Measuring Cell Migration.

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Chowdhury, Aniqa N; Vo, Huu Tri; Olang, Sharon; Mappus, Elliott; Peterson, Brian; Hlavac, Nora; Harvey, Tyler; Dean, Delphine

2017-03-12

Cell migration is a vital part of immune responses, growth, and wound healing. Cell migration is a complex process that involves interactions between cells, the extracellular matrix, and soluble and non-soluble chemical factors (e.g., chemoattractants). Standard methods for measuring the migration of cells, such as the Boyden chamber assay, work by counting cells on either side of a divider. These techniques are easy to use; however, they offer little geometric modification for different applications. In contrast, microfluidic devices can be used to observe cell migration with customizable concentration gradients of soluble factors 1 , 2 . However, methods for making microfluidics based assays can be difficult to learn. Here, we describe an easy method for creating cell culture chambers to measure cell migration in response to chemical concentration gradients. Our cell migration chamber method can create different linear concentration gradients in order to study cell migration for a variety of applications. This method is relatively easy to use and is typically performed by undergraduate students. The microchannel chamber was created by placing an acrylic insert in the shape of the final microchannel chamber well into a Petri dish. After this, poly(dimethylsiloxane) (PDMS) was poured on top of the insert. The PDMS was allowed to harden and then the insert was removed. This allowed for the creation of wells in any desired shape or size. Cells may be subsequently added to the microchannel chamber, and soluble agents can be added to one of the wells by soaking an agarose block in the desired agent. The agarose block is added to one of the wells, and time-lapse images can be taken of the microchannel chamber in order to quantify cell migration. Variations to this method can be made for a given application, making this method highly customizable.

Lutein Inhibits the Migration of Retinal Pigment Epithelial Cells via Cytosolic and Mitochondrial Akt Pathways (Lutein Inhibits RPE Cells Migration

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Ching-Chieh Su

2014-08-01

Full Text Available During the course of proliferative vitreoretinopathy (PVR, the retinal pigment epithelium (RPE cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation.

Impact of cell shape on cell migration behavior on elastic substrate

International Nuclear Information System (INIS)

Zhong Yuan; Ji Baohua

2013-01-01

Cell shape is known to have profound effects on a number of cell behaviors. In this paper we have studied its role in cell migration through modeling the effect of cell shape on the cell traction force distribution, the traction force dependent stability of cell adhesion and the matrix rigidity dependent traction force formation. To quantify the driving force of cell migration, a new parameter called the motility factor, that takes account of the effect of cell shape, matrix rigidity and dynamic stability of cell adhesion, is proposed. We showed that the motility factor depends on the matrix rigidity in a biphasic manner, which is consistent with the experimental observations of the biphasic dependence of cell migration speed on the matrix rigidity. We showed that the cell shape plays a pivotal role in the cell migration behavior by regulating the traction force at the cell front and rear. The larger the cell polarity, the larger the motility factor is. The keratocyte-like shape has a larger motility factor than the fibroblast-like shape, which explains why keratocyte has a much higher migration speed. The motility factor might be an appropriate parameter for a quantitative description of the driving force of cell migration. (paper)

Migration of Cells in a Social Context

DEFF Research Database (Denmark)

Vedel, Søren; Tay, Savas; Johnston, Darius M.

2013-01-01

In multicellular organisms and complex ecosystems, cells migrate in a social context. While this is essential for the basic processes of life such as embryonic development, wound healing and unregulated migration furthermore is implicated in diseases such as cancer, the influence of neighboring...... cells on the individual remains poorly understood. Previous work on isolated cells has revealed a stereotypical migratory behavior, however many aspects of the migration characteristics of cells in populations remained unknown exactly because of this lack of characterization of neighbour-cell influence....... We quantified1 the migration of thousands of individual cells in their population context using time-lapse microscopy, microfluidic cell culture and automated image analysis, and discovered a much richer dynamics in the social context, with significant variations in directionality, displacement...

Follow-the-leader cell migration requires biased cell-cell contact and local microenvironmental signals

Science.gov (United States)

Wynn, Michelle L.; Rupp, Paul; Trainor, Paul A.; Schnell, Santiago; Kulesa, Paul M.

2013-06-01

Directed cell migration often involves at least two types of cell motility that include multicellular streaming and chain migration. However, what is unclear is how cell contact dynamics and the distinct microenvironments through which cells travel influence the selection of one migratory mode or the other. The embryonic and highly invasive neural crest (NC) are an excellent model system to study this question since NC cells have been observed in vivo to display both of these types of cell motility. Here, we present data from tissue transplantation experiments in chick and in silico modeling that test our hypothesis that cell contact dynamics with each other and the microenvironment promote and sustain either multicellular stream or chain migration. We show that when premigratory cranial NC cells (at the pre-otic level) are transplanted into a more caudal region in the head (at the post-otic level), cells alter their characteristic stream behavior and migrate in chains. Similarly, post-otic NC cells migrate in streams after transplantation into the pre-otic hindbrain, suggesting that local microenvironmental signals dictate the mode of NC cell migration. Simulations of an agent-based model (ABM) that integrates the NC cell behavioral data predict that chain migration critically depends on the interplay of biased cell-cell contact and local microenvironment signals. Together, this integrated modeling and experimental approach suggests new experiments and offers a powerful tool to examine mechanisms that underlie complex cell migration patterns.

Forebrain neurogenesis: From embryo to adult.

Science.gov (United States)

Dennis, Daniel; Picketts, David; Slack, Ruth S; Schuurmans, Carol

2016-01-01

A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16-17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis : From embryo to adult . The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with 'state of the art' techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

Absence of the neurogenesis-dependent nuclear receptor TLX induces inflammation in the hippocampus.

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Kozareva, Danka A; Hueston, Cara M; Ó'Léime, Ciarán S; Crotty, Suzanne; Dockery, Peter; Cryan, John F; Nolan, Yvonne M

2017-08-20

The orphan nuclear receptor TLX (Nr2e1) is a key regulator of hippocampal neurogenesis. Impaired adult hippocampal neurogenesis has been reported in neurodegenerative and psychiatric conditions including dementia and stress-related depression. Neuroinflammation is also implicated in the neuropathology of these disorders, and has been shown to negatively affect hippocampal neurogenesis. To investigate a role for TLX in hippocampal neuroinflammation, we assessed microglial activation in the hippocampus of mice with a spontaneous deletion of TLX. Results from our study suggest that a lack of TLX is implicated in deregulation of microglial phenotype and that consequently, the survival and function of newborn cells in the hippocampus is impaired. TLX may be an important target in understanding inflammatory-associated impairments in neurogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

On the Role of Neurogenesis and Neural Plasticity in the Evolution of Animal Personalities and Stress Coping Styles

DEFF Research Database (Denmark)

Overli, Oyvind; Sorensen, Christina

2016-01-01

and neurogenesis have received recent attention. This work reveals that brain cell proliferation and neurogenesis are associated with heritable variation in stress coping style, and they are also differentially affected by short- and long-term stress in a biphasic manner. Routine-dependent and inflexible behavior...... are conserved throughout the vertebrate subphylum, including factors affecting perception, learning, and memory of stimuli and events. Here we review conserved aspects of the contribution of neurogenesis and other aspects of neural plasticity to stress coping. In teleost fish, brain cell proliferation...

Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration

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Jo Richardson

2016-05-01

Full Text Available Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

Neurogenesis in spinal cord of mouse: an autoradiographic analysis

International Nuclear Information System (INIS)

Nornes, H.O.; Carry, M.

1978-01-01

An autoradiographic analysis of the time and sites of origin, and the migration and setting patterns of neurons was made in the spinal cord of the mouse. The neurons originated on days 10-15 of gestation with temporal gradients along the ventrodorsal and rostrocaudal axes. The motor neurons originated on days 10-11 of gestation; the neurons in the intermediate gray region originated on days 11-14 of gestation; the neurons of the head of the dorsal horn originated on days 12-14 of gestation. The neurons that originated on days 10 and 11 originated and migrated primarily from the basal plate, and they settled in the adjacent regions of the intermediate zone; those neurons formed on days 12-14 originated and migrated primarily from the alar plate, and it was concluded that these neuroblasts similarly settled in the adjacent regions of the intermediate zone. Extraventricular proliferation, which presumably signaled the initial stages of gliogenesis, was first observed on day 12 of gestation. This study supports the classical idea of the mosaic pattern of neurogenesis in the embryonic spinal cord. (Auth.)

Intermittent fasting attenuates increases in neurogenesis after ischemia and reperfusion and improves recovery.

Science.gov (United States)

Manzanero, Silvia; Erion, Joanna R; Santro, Tomislav; Steyn, Frederik J; Chen, Chen; Arumugam, Thiruma V; Stranahan, Alexis M

2014-05-01

Intermittent fasting (IF) is neuroprotective across a range of insults, but the question of whether extending the interval between meals alters neurogenesis after ischemia remains unexplored. We therefore measured cell proliferation, cell death, and neurogenesis after transient middle cerebral artery occlusion (MCAO) or sham surgery (SHAM) in mice fed ad libitum (AL) or maintained on IF for 3 months. IF was associated with twofold reductions in circulating levels of the adipocyte cytokine leptin in intact mice, but also prevented further reductions in leptin after MCAO. IF/MCAO mice also exhibit infarct volumes that were less than half those of AL/MCAO mice. We observed a 30% increase in basal cell proliferation in the hippocampus and subventricular zone (SVZ) in IF/SHAM, relative to AL/SHAM mice. However, cell proliferation after MCAO was limited in IF mice, which showed twofold increases in cell proliferation relative to IF/SHAM, whereas AL/MCAO mice exhibit fivefold increases relative to AL/SHAM. Attenuation of stroke-induced neurogenesis was correlated with reductions in cell death, with AL/MCAO mice exhibiting twice the number of dying cells relative to IF/MCAO mice. These observations indicate that IF protects against neurological damage in ischemic stroke, with circulating leptin as one possible mediator.

Role of adult hippocampal neurogenesis in stress resilience

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Brunno R. Levone

2015-01-01

Full Text Available There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders.

Human neutrophils facilitate tumor cell transendothelial migration.

LENUS (Irish Health Repository)

Wu, Q D

2012-02-03

Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation

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Jessberger Sebastian

2006-11-01

Full Text Available Abstract Background In the course of adult hippocampal neurogenesis most regulation takes place during the phase of doublecortin (DCX expression, either as pro-proliferative effect on precursor cells or as survival-promoting effect on postmitotic cells. We here obtained quantitative data about the proliferative population and the dynamics of postmitotic dendrite development during the period of DCX expression. The question was, whether any indication could be obtained that the initiation of dendrite development is timely bound to the exit from the cell cycle. Alternatively, the temporal course of morphological maturation might be subject to additional regulatory events. Results We found that (1 20% of the DCX population were precursor cells in cell cycle, whereas more than 70% were postmitotic, (2 the time span until newborn cells had reached the most mature stage associated with DCX expression varied between 3 days and several weeks, (3 positive or negative regulation of precursor cell proliferation did not alter the pattern and dynamics of dendrite development. Dendrite maturation was largely independent of close contacts to astrocytes. Conclusion These data imply that dendrite maturation of immature neurons is initiated at varying times after cell cycle exit, is variable in duration, and is controlled independently of the regulation of precursor cell proliferation. We conclude that in addition to the major regulatory events in cell proliferation and selective survival, additional micro-regulatory events influence the course of adult hippocampal neurogenesis.

Adult Neurogenesis and Mental Illness

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Schoenfeld, Timothy J; Cameron, Heather A

2015-01-01

Several lines of evidence suggest that adult neurogenesis, the production of new neurons in adulthood, may play a role in psychiatric disorders, including depression, anxiety, and schizophrenia. Medications and other treatments for mental disorders often promote the proliferation of new neurons; the time course for maturation and integration of new neurons in circuitry parallels the delayed efficacy of psychiatric therapies; adverse and beneficial experiences similarly affect development of mental illness and neurogenesis; and ablation of new neurons in adulthood alters the behavioral impact of drugs in animal models. At present, the links between adult neurogenesis and depression seem stronger than those suggesting a relationship between new neurons and anxiety or schizophrenia. Yet, even in the case of depression there is currently no direct evidence for a causative role. This article reviews the data relating adult neurogenesis to mental illness and discusses where research needs to head in the future. PMID:25178407

Extremely weak magnetic field exposure may inhibit hippocampal neurogenesis of Sprague Dawley rats

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Zhang, B.; Tian, L.; Cai, Y.; Xu, H.; Pan, Y.

2016-12-01

Hippocampal neurogenesis occurs throughout life in mammals brains and can be influenced by animals' age as well as environmental factors. Lines of evidences have shown that the magnetic field is an important physics environmental factor influencing many animals' growth and development, and extremely weak magnetic field exposures have been proved having serious adverse effects on the metabolism and behaviors in some animals, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we experimentally examined the extremely weak magnetic field effects on neurogenesis of the dentate gyrus (DG) of hippocampus of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, an extremely weak magnetic field (≤ 0.5μT) and the geomagnetic fields (strength 31-58μT) as controls. Thirty-two SD rats (3-weeks old) were used in this study. New cell survival in hippocampus was assessed at 0, 14, 28, and 42 days after a 7-day intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU). Meanwhile, the amounts of immature neurons and mature neurons which are both related to hippocampal neurogenesis, as documented by labeling with doublecortin (DCX) and neuron (NeuN), respectively, were also analyzed at 0, 14, 28, and 42 days. Compared with geomagnetic field exposure groups, numbers of BrdU-, DCX-positive cells of DG of hippocampus in tested rats reduces monotonously and more rapidly after 14 days, and NeuN-positive cells significantly decreases after 28days when exposed in the extremely weak magnetic field condition. Our data suggest that the exposure to an extremely weak magnetic field may suppress the neurogenesis in DG of SD rats.

Histone deacetylases control neurogenesis in embryonic brain by inhibition of BMP2/4 signaling.

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Maya Shakèd

Full Text Available BACKGROUND: Histone-modifying enzymes are essential for a wide variety of cellular processes dependent upon changes in gene expression. Histone deacetylases (HDACs lead to the compaction of chromatin and subsequent silencing of gene transcription, and they have recently been implicated in a diversity of functions and dysfunctions in the postnatal and adult brain including ocular dominance plasticity, memory consolidation, drug addiction, and depression. Here we investigate the role of HDACs in the generation of neurons and astrocytes in the embryonic brain. PRINCIPAL FINDINGS: As a variety of HDACs are expressed in differentiating neural progenitor cells, we have taken a pharmacological approach to inhibit multiple family members. Inhibition of class I and II HDACs in developing mouse embryos with trichostatin A resulted in a dramatic reduction in neurogenesis in the ganglionic eminences and a modest increase in neurogenesis in the cortex. An identical effect was observed upon pharmacological inhibition of HDACs in in vitro-differentiating neural precursors derived from the same brain regions. A reduction in neurogenesis in ganglionic eminence-derived neural precursors was accompanied by an increase in the production of immature astrocytes. We show that HDACs control neurogenesis by inhibition of the bone morphogenetic protein BMP2/4 signaling pathway in radial glial cells. HDACs function at the transcriptional level by inhibiting and promoting, respectively, the expression of Bmp2 and Smad7, an intracellular inhibitor of BMP signaling. Inhibition of the BMP2/4 signaling pathway restored normal levels of neurogenesis and astrogliogenesis to both ganglionic eminence- and cortex-derived cultures in which HDACs were inhibited. CONCLUSIONS: Our results demonstrate a transcriptionally-based regulation of BMP2/4 signaling by HDACs both in vivo and in vitro that is critical for neurogenesis in the ganglionic eminences and that modulates cortical

Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy.

Science.gov (United States)

Paradisi, M; Fernández, M; Del Vecchio, G; Lizzo, G; Marucci, G; Giulioni, M; Pozzati, E; Antonelli, T; Lanzoni, G; Bagnara, G P; Giardino, L; Calzà, L

2010-10-01

Neurogenesis in adult humans occurs in at least two areas of the brain, the subventricular zone of the telencephalon and the subgranular layer of the dentate gyrus in the hippocampal formation. We studied dentate gyrus subgranular layer neurogenesis in patients subjected to tailored antero-mesial temporal resection including amygdalohippocampectomy due to pharmacoresistant temporal lobe epilepsy (TLE) using the in vitro neurosphere assay. Sixteen patients were enrolled in the study; mesial temporal sclerosis (MTS) was present in eight patients. Neurogenesis was investigated by ex vivo neurosphere expansion in the presence of mitogens (epidermal growth factor + basic fibroblast growth factor) and spontaneous differentiation after mitogen withdrawal. Growth factor synthesis was investigated by qRT-PCR in neurospheres. We demonstrate that in vitro proliferation of cells derived from dentate gyrus of TLE patients is dependent on disease duration. Moreover, the presence of MTS impairs proliferation. As long as in vitro proliferation occurs, neurogenesis is maintained, and cells expressing a mature neurone phenotype (TuJ1, MAP2, GAD) are spontaneously formed after mitogen withdrawal. Finally, formed neurospheres express mRNAs encoding for growth (vascular endothelial growth factor) as well as neurotrophic factors (brain-derived neurotrophic factor, ciliary neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor). We demonstrated that residual neurogenesis in the subgranular layer of the dentate gyrus in TLE is dependent on diseases duration and absent in MTS. © 2010 The Authors. Neuropathology and Applied Neurobiology © 2010 British Neuropathological Society.

Do migrating cells need a nucleus?

Science.gov (United States)

Hawkins, Rhoda J

2018-03-05

How the nucleus affects cell polarity and migration is unclear. In this issue, Graham et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201706097) show that enucleated cells polarize and migrate in two but not three dimensions and propose that the nucleus is a necessary component of the molecular clutch regulating normal mechanical responses. © 2018 Hawkins.

Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells of the hippocampal neurogenesis in rat offspring via dysfunction of cholinergic inputs by myelin vacuolation

International Nuclear Information System (INIS)

Itahashi, Megu; Abe, Hajime; Tanaka, Takeshi; Mizukami, Sayaka; Kimura, Masayuki; Yoshida, Toshinori; Shibutani, Makoto

2015-01-01

Highlights: • The effect of maternal exposure to HCP on rat hippocampal neurogenesis was examined. • HCP induces myelin vacuolation of nerve tracts in the septal–hippocampal pathway. • Myelin changes suppress Chrnb2-mediated cholinergic inputs to the dentate gyrus. • SGZ apoptosis occurs via the mitochondrial pathway and targets type-2b cells. • Dysfunction of cholinergic inputs is related to type-2b SGZ cell apoptosis. - Abstract: Hexachlorophene (HCP) is known to induce myelin vacuolation corresponding to intramyelinic edema of nerve fibers in the central and peripheral nervous system in animals. This study investigated the effect of maternal exposure to HCP on hippocampal neurogenesis in rat offspring using pregnant rats supplemented with 0 (controls), 100, or 300 ppm HCP in the diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, the numbers of T box brain 2 + progenitor cells and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling + apoptotic cells in the hippocampal subgranular zone (SGZ) decreased in female offspring at 300 ppm, which was accompanied by myelin vacuolation and punctate tubulin beta-3 chain staining of nerve fibers in the hippocampal fimbria. In addition, transcript levels of the cholinergic receptor, nicotinic beta 2 (Chrnb2) and B-cell CLL/lymphoma 2 (Bcl2) decreased in the dentate gyrus. HCP-exposure did not alter the numbers of SGZ proliferating cells and reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)-ergic interneuron subpopulations in the dentate hilus on PND 21 and PND 77. Although some myelin vacuolation remained, all other changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77. These results suggest that maternal HCP exposure reversibly decreases type-2b intermediate-stage progenitor cells via the mitochondrial apoptotic pathway in offspring hippocampal neurogenesis at 300 ppm HCP. Neurogenesis may be affected by dysfunction

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

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Esteban M Rodríguez

2012-01-01

Full Text Available Most cells of the developing mammalian brain derive from the ventricular (VZ and the subventricular (SVZ zones. The VZ is formed by the multipotent radial glia/neural stem cells (NSCs while the SVZ harbors the rapidly proliferative neural precursor cells (NPCs. Evidence from human and animal models indicates that the common history of hydrocephalus and brain maldevelopment starts early in embryonic life with disruption of the VZ and SVZ. We propose that a "cell junction pathology" involving adherent and gap junctions is a final common outcome of a wide range of gene mutations resulting in proteins abnormally expressed by the VZ cells undergoing disruption. Disruption of the VZ during fetal development implies the loss of NSCs whereas VZ disruption during the perinatal period implies the loss of ependyma. The process of disruption occurs in specific regions of the ventricular system and at specific stages of brain development. This explains why only certain brain structures have an abnormal development, which in turn results in a specific neurological impairment of the newborn. Disruption of the VZ of the Sylvian aqueduct (SA leads to aqueductal stenosis and hydrocephalus, while disruption of the VZ of telencephalon impairs neurogenesis. We are currently investigating whether grafting of NSCs/neurospheres from normal rats into the CSF of hydrocephalic mutants helps to diminish/repair the outcomes of VZ disruption.

Deletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampus.

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Kozareva, Danka A; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

2018-01-01

Adolescence is a sensitive period of neurodevelopment during which life experiences can have profound effects on the brain. Hippocampal neurogenesis, the neurodevelopmental process of generating functional new neurons from neural stem cells, occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. The aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (isolation stress) wild type and Nr2e1 -/- mice or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 weeks during adolescence. A reduction of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1 -/- mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life. © 2017 Wiley Periodicals, Inc.

Putative Adult Neurogenesis in Old World Parrots: The Congo African Grey Parrot (Psittacus erithacus and Timneh Grey Parrot (Psittacus timneh

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Pedzisai Mazengenya

2018-02-01

Full Text Available In the current study, we examined for the first time, the potential for adult neurogenesis throughout the brain of the Congo African grey parrot (Psittacus erithacus and Timneh grey parrot (Psittacus timneh using immunohistochemistry for the endogenous markers proliferating cell nuclear antigen (PCNA, which labels proliferating cells, and doublecortin (DCX, which stains immature and migrating neurons. A similar distribution of PCNA and DCX immunoreactivity was found throughout the brain of the Congo African grey and Timneh grey parrots, but minor differences were also observed. In both species of parrots, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, subventricular zone of the lateral wall of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and the rhombencephalon. The olfactory bulb and telencephalic subdivisions exhibited a higher density of both PCNA and DCX immunoreactive cells than any other brain region. DCX immunoreactive staining was stronger in the telencephalon than in the subtelencephalic structures. There was evidence of proliferative hot spots in the dorsal and ventral poles of the lateral ventricle in the Congo African grey parrots at rostral levels, whereas only the dorsal accumulation of proliferating cells was observed in the Timneh grey parrot. In most pallial regions the density of PCNA and DCX stained cells increased from rostral to caudal levels with the densest staining in the nidopallium caudolaterale (NCL. The widespread distribution of PCNA and DCX in the brains of both parrot species suggest the importance of adult neurogenesis and neuronal plasticity during learning and adaptation to external environmental variations.

Putative Adult Neurogenesis in Old World Parrots: The Congo African Grey Parrot (Psittacus erithacus) and Timneh Grey Parrot (Psittacus timneh).

Science.gov (United States)

Mazengenya, Pedzisai; Bhagwandin, Adhil; Manger, Paul R; Ihunwo, Amadi O

2018-01-01

In the current study, we examined for the first time, the potential for adult neurogenesis throughout the brain of the Congo African grey parrot ( Psittacus erithacus ) and Timneh grey parrot ( Psittacus timneh ) using immunohistochemistry for the endogenous markers proliferating cell nuclear antigen (PCNA), which labels proliferating cells, and doublecortin (DCX), which stains immature and migrating neurons. A similar distribution of PCNA and DCX immunoreactivity was found throughout the brain of the Congo African grey and Timneh grey parrots, but minor differences were also observed. In both species of parrots, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, subventricular zone of the lateral wall of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and the rhombencephalon. The olfactory bulb and telencephalic subdivisions exhibited a higher density of both PCNA and DCX immunoreactive cells than any other brain region. DCX immunoreactive staining was stronger in the telencephalon than in the subtelencephalic structures. There was evidence of proliferative hot spots in the dorsal and ventral poles of the lateral ventricle in the Congo African grey parrots at rostral levels, whereas only the dorsal accumulation of proliferating cells was observed in the Timneh grey parrot. In most pallial regions the density of PCNA and DCX stained cells increased from rostral to caudal levels with the densest staining in the nidopallium caudolaterale (NCL). The widespread distribution of PCNA and DCX in the brains of both parrot species suggest the importance of adult neurogenesis and neuronal plasticity during learning and adaptation to external environmental variations.

Long-Term Live Cell Imaging of Cell Migration: Effects of Pathogenic Fungi on Human Epithelial Cell Migration.

Science.gov (United States)

Wöllert, Torsten; Langford, George M

2016-01-01

Long-term live cell imaging was used in this study to determine the responses of human epithelial cells to pathogenic biofilms formed by Candida albicans. Epithelial cells of the skin represent the front line of defense against invasive pathogens such as C. albicans but under certain circumstances, especially when the host's immune system is compromised, the skin barrier is breached. The mechanisms by which the fungal pathogen penetrates the skin and invade the deeper layers are not fully understood. In this study we used keratinocytes grown in culture as an in vitro model system to determine changes in host cell migration and the actin cytoskeleton in response to virulence factors produced by biofilms of pathogenic C. albicans. It is clear that changes in epithelial cell migration are part of the response to virulence factors secreted by biofilms of C. albicans and the actin cytoskeleton is the downstream effector that mediates cell migration. Our goal is to understand the mechanism by which virulence factors hijack the signaling pathways of the actin cytoskeleton to alter cell migration and thereby invade host tissues. To understand the dynamic changes of the actin cytoskeleton during infection, we used long-term live cell imaging to obtain spatial and temporal information of actin filament dynamics and to identify signal transduction pathways that regulate the actin cytoskeleton and its associated proteins. Long-term live cell imaging was achieved using a high resolution, multi-mode epifluorescence microscope equipped with specialized light sources, high-speed cameras with high sensitivity detectors, and specific biocompatible fluorescent markers. In addition to the multi-mode epifluorescence microscope, a spinning disk confocal long-term live cell imaging system (Olympus CV1000) equipped with a stage incubator to create a stable in vitro environment for long-term real-time and time-lapse microscopy was used. Detailed descriptions of these two long-term live

Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior.

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Deroche-Gamonet, Véronique; Revest, Jean-Michel; Fiancette, Jean-François; Balado, Eric; Koehl, Muriel; Grosjean, Noëlle; Abrous, Djoher Nora; Piazza, Pier-Vincenzo

2018-03-05

The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine-related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction.

Paracrine control of vascularization and neurogenesis by neurotrophins.

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Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

2003-10-01

The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

Factors That Modulate Neurogenesis: A Top-Down Approach.

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LaDage, Lara D

2016-08-24

Although hippocampal neurogenesis in the adult brain has been conserved across the vertebrate lineage, laboratory studies have primarily examined this phenomenon in rodent models. This approach has been successful in elucidating important factors and mechanisms that can modulate rates of hippocampal neurogenesis, including hormones, environmental complexity, learning and memory, motor stimulation, and stress. However, recent studies have found that neurobiological research on neurogenesis in rodents may not easily translate to, or explain, neurogenesis patterns in nonrodent systems, particularly in species examined in the field. This review examines some of the evolutionary and ecological variables that may also modulate neurogenesis patterns. This 'top-down' and more naturalistic approach, which incorporates ecology and natural history, particularly of nonmodel species, may allow for a more comprehensive understanding of the functional significance of neurogenesis. © 2016 S. Karger AG, Basel.

Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal

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Hanson, Nicola D; Owens, Michael J; Nemeroff, Charles B

2011-01-01

The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment. PMID:21937982

Insulin promotes cell migration by regulating PSA-NCAM

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Monzo, Hector J.; Coppieters, Natacha [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Park, Thomas I.H. [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Dieriks, Birger V.; Faull, Richard L.M. [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Dragunow, Mike [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Curtis, Maurice A., E-mail: m.curtis@auckland.ac.nz [Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand); Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland (New Zealand)

2017-06-01

Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of αv-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that αv-integrin plays a key role in the PSA-NCAM turnover process. αv-integrin knockdown stopped PSA-NCAM from being endocytosed, and αv-integrin/PSA-NCAM clusters co-labelled intracellularly with Rab5, altogether indicating a role for αv-integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of αv-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. - Highlights: • Insulin modulates PSA-NCAM turnover through upregulation of p-FAK. • P-FAK modulates αv-integrin/PSA-NCAM clustering. • αv-integrin acts as a carrier for PSA-NCAM endocytosis. • Cell migration is promoted by cell surface PSA. • Insulin promotes PSA-dependent migration in vitro.

Insulin promotes cell migration by regulating PSA-NCAM

International Nuclear Information System (INIS)

Monzo, Hector J.; Coppieters, Natacha; Park, Thomas I.H.; Dieriks, Birger V.; Faull, Richard L.M.; Dragunow, Mike; Curtis, Maurice A.

2017-01-01

Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of αv-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that αv-integrin plays a key role in the PSA-NCAM turnover process. αv-integrin knockdown stopped PSA-NCAM from being endocytosed, and αv-integrin/PSA-NCAM clusters co-labelled intracellularly with Rab5, altogether indicating a role for αv-integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of αv-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. - Highlights: • Insulin modulates PSA-NCAM turnover through upregulation of p-FAK. • P-FAK modulates αv-integrin/PSA-NCAM clustering. • αv-integrin acts as a carrier for PSA-NCAM endocytosis. • Cell migration is promoted by cell surface PSA. • Insulin promotes PSA-dependent migration in vitro.

Correlations between Hippocampal Neurogenesis and Metabolic Indices in Adult Nonhuman Primates

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Tarique D. Perera

2011-01-01

Full Text Available Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010, but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX, and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2, but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein. This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.

Low-Dose Sevoflurane Promotes Hippocampal Neurogenesis and Facilitates the Development of Dentate Gyrus-Dependent Learning in Neonatal Rats

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Chong Chen

2015-04-01

Full Text Available Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8% sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4–6 were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.

Transcriptomic Analysis Of Purified Embryonic Neural Stem Cells From Zebrafish Embryos Reveals Signalling Pathways Involved In Glycine-dependent Neurogenesis

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Eric eSAMARUT

2016-03-01

Full Text Available How is the initial set of neurons correctly established during the development of the vertebrate central nervous system? In the embryo, glycine and GABA are depolarizing due the immature chloride gradient, which is only reversed to become hyperpolarizing later in post-natal development. We previously showed that glycine regulates neurogenesis via paracrine signalling that promotes calcium transients in neural stem cells (NSCs and their differentiation into interneurons within the spinal cord of the zebrafish embryo. However, the subjacent molecular mechanisms are not yet understood. Our previous work suggests that early neuronal progenitors were not differentiating correctly in the developing spinal cord. As a result, we aimed at identifying the downstream molecular mechanisms involved specifically in NSCs during glycine-dependent embryonic neurogenesis. Using a gfap:GFP transgenic line, we successfully purified NSCs by fluorescence-activated cell sorting (FACS from whole zebrafish embryos and in embryos in which the glycine receptor was knocked down. The strength of this approach is that it focused on the NSC population while tackling the biological issue in an in vivo context in whole zebrafish embryos. After sequencing the transcriptome by RNA-sequencing, we analyzed the genes whose expression was changed upon disruption of glycine signalling and we confirmed the differential expression by independent RTqPCR assay. While over a thousand genes showed altered expression levels, through pathway analysis we identified 14 top candidate genes belonging to five different canonical signalling pathways (signalling by calcium, TGF-beta, sonic hedgehog, Wnt and p53-related apoptosis that are likely to mediate the promotion of neurogenesis by glycine.

Untangling cell tracks: Quantifying cell migration by time lapse image data analysis.

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Svensson, Carl-Magnus; Medyukhina, Anna; Belyaev, Ivan; Al-Zaben, Naim; Figge, Marc Thilo

2018-03-01

Automated microscopy has given researchers access to great amounts of live cell imaging data from in vitro and in vivo experiments. Much focus has been put on extracting cell tracks from such data using a plethora of segmentation and tracking algorithms, but further analysis is normally required to draw biologically relevant conclusions. Such relevant conclusions may be whether the migration is directed or not, whether the population has homogeneous or heterogeneous migration patterns. This review focuses on the analysis of cell migration data that are extracted from time lapse images. We discuss a range of measures and models used to analyze cell tracks independent of the biological system or the way the tracks were obtained. For single-cell migration, we focus on measures and models giving examples of biological systems where they have been applied, for example, migration of bacteria, fibroblasts, and immune cells. For collective migration, we describe the model systems wound healing, neural crest migration, and Drosophila gastrulation and discuss methods for cell migration within these systems. We also discuss the role of the extracellular matrix and subsequent differences between track analysis in vitro and in vivo. Besides methods and measures, we are putting special focus on the need for openly available data and code, as well as a lack of common vocabulary in cell track analysis. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

Low Doses of Curcuma longa Modulates Cell Migration and Cell-Cell Adhesion.

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de Campos, Paloma Santos; Matte, Bibiana Franzen; Diel, Leonardo Francisco; Jesus, Luciano Henrique; Bernardi, Lisiane; Alves, Alessandro Menna; Rados, Pantelis Varvaki; Lamers, Marcelo Lazzaron

2017-09-01

Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC. Curcumin (2 μM) decreased cell proliferation in cell lines with mesenchymal characteristics, while cell death was detected only at 50 μM. We observed that highly migratory cells showed a decrease on migration speed and directionality when treated with 2 or 5 μM of curcumin (50% and 40%, respectively, p curcumin dose dependently decreased cell-cell adhesion, especially on tumor-derived spheroids. Also, in a xenograft model with patient-derived OSCC cells, the administration of curcumin decreased tumor growth and aggressiveness when compared with untreated tumors, indicating the potential antitumor effect in oral cancer. These results suggest that lower doses of curcumin can influence several steps involved in tumorigenesis, including migration properties, suggesting a possible use in cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Differential migration and proliferation of geometrical ensembles of cell clusters

International Nuclear Information System (INIS)

Kumar, Girish; Chen, Bo; Co, Carlos C.; Ho, Chia-Chi

2011-01-01

Differential cell migration and growth drives the organization of specific tissue forms and plays a critical role in embryonic development, tissue morphogenesis, and tumor invasion. Localized gradients of soluble factors and extracellular matrix have been shown to modulate cell migration and proliferation. Here we show that in addition to these factors, initial tissue geometry can feedback to generate differential proliferation, cell polarity, and migration patterns. We apply layer by layer polyelectrolyte assembly to confine multicellular organization and subsequently release cells to demonstrate the spatial patterns of cell migration and growth. The cell shapes, spreading areas, and cell-cell contacts are influenced strongly by the confining geometry. Cells within geometric ensembles are morphologically polarized. Symmetry breaking was observed for cells on the circular pattern and cells migrate toward the corners and in the direction parallel to the longest dimension of the geometric shapes. This migration pattern is disrupted when actomyosin based tension was inhibited. Cells near the edge or corner of geometric shapes proliferate while cells within do not. Regions of higher rate of cell migration corresponded to regions of concentrated growth. These findings demonstrate that multicellular organization can result in spatial patterns of migration and proliferation.

The satiating hormone amylin enhances neurogenesis in the area postrema of adult rats

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Claudia G. Liberini

2016-10-01

Full Text Available Objective: Adult neurogenesis in the subgranular zone and subventricular zone is generally accepted, but its existence in other brain areas is still controversial. Circumventricular organs, such as the area postrema (AP have recently been described as potential neurogenic niches in the adult brain. The AP is the major site of action of the satiating hormone amylin. Amylin has been shown to promote the formation of neuronal projections originating from the AP in neonatal rodents but the role of amylin in adult neurogenesis remains unknown. Methods: To test this, we first performed an RNA-sequencing of the AP of adult rats acutely injected with either amylin (20 μg/kg, amylin plus the amylin receptor antagonist AC187 (500 μg/kg or vehicle. Second, animals were subcutaneously equipped with minipumps releasing either amylin (50 μg/kg/day or vehicle for 3 weeks to assess cell proliferation and differentiation with the 5′-bromo-2-deoxyuridine (BrdU technique. Results: Acute amylin injections affected genes involved in pathways and processes that control adult neurogenesis. Amylin consistently upregulated NeuroD1 transcript and protein in the adult AP, and this effect was blocked by the co-administration of AC187. Further, chronic amylin treatment increased the number of newly proliferated AP-cells and significantly promoted their differentiation into neurons rather than astrocytes. Conclusion: Our findings revealed a novel role of the satiating hormone amylin in promoting neurogenesis in the AP of adult rats. Keywords: Amylin, Adult neurogenesis, Area postrema, BrdU, Circumventricular organs

Adult Neurogenesis Supports Short-Term Olfactory Memory

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Arenkiel, Benjamin R.

2010-01-01

Adult neurogenesis has captivated neuroscientists for decades, with hopes that understanding the programs underlying this phenomenon may provide unique insight toward avenues for brain repair. Interestingly, however, despite intense molecular and cellular investigation, the evolutionary roles and biological functions for ongoing neurogenesis have remained elusive. Here I review recent work published in the Journal of Neuroscience that reveals a functional role for continued neurogenesis towar...

Early Postnatal but Not Late Adult Neurogenesis Is Impaired in the Pitx3-Mutant Animal Model of Parkinson's Disease

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Moritz D. Brandt

2017-08-01

Full Text Available The generation of new neurons in the adult dentate gyrus has functional implications for hippocampal formation. Reduced hippocampal neurogenesis has been described in various animal models of hippocampal dysfunction such as dementia and depression, which are both common non-motor-symptoms of Parkinson's disease (PD. As dopamine plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN in PD may be related to the reduced neurogenesis observed in the neurogenic regions of the adult brain: subventricular zone (SVZ and dentate gyrus (DG. Here we examined adult hippocampal neurogenesis in the Pitx3-mutant mouse model of PD (aphakia mice, which phenotypically shows a selective embryonic degeneration of dopamine neurons within the SN and to a smaller extent in the ventral tegmental area (VTA. Proliferating cells were labeled with BrdU in aphakia mice and healthy controls from 3 to 42 weeks of age. Three weeks old mutant mice showed an 18% reduction of proliferating cells in the DG and of 26% in the SVZ. Not only proliferation but also the number of new neurons was impaired in young aphakia mice resulting in 33% less newborn cells 4 weeks after BrdU-labeling. Remarkably, however, the decline in the number of proliferating cells in the neurogenic regions vanished in older animals (8–42 weeks indicating that aging masks the effect of dopamine depletion on adult neurogenesis. Region specific reduction in precursor cells proliferation correlated with the extent of dopaminergic degeneration in mesencephalic subregions (VTA and SN, which supports the theory of age- and region-dependent regulatory effects of dopaminergic projections. Physiological stimulation of adult neurogenesis by physical activity (wheel running almost doubled the number of proliferating cells in the dentate gyrus of 8 weeks old aphakia mice to a number comparable to that of wild-type mice, abolishing the slight

Repeated exposure of the developing rat brain to magnetic resonance imaging did not affect neurogenesis, cell death or memory function

International Nuclear Information System (INIS)

Zhu, Changlian; Gao, Jianfeng; Li, Qian; Huang, Zhiheng; Zhang, Yu; Li, Hongfu; Kuhn, Hans-Georg; Blomgren, Klas

2011-01-01

Research highlights: → The effect of MRI on the developing brain is a matter of debate. → Repeated exposure to MRI did not affect neurogenesis. → Memory function was not affected by repeated MRI during development. → Neither late gestation nor young postnatal brains were affected by MRI. → Repeated MRI did not cause cell death in the neurogenic region of the hippocampus. -- Abstract: The effect of magnetic fields on the brain is a matter of debate. The objective of this study was to investigate whether repeated exposure to strong magnetic fields, such as during magnetic resonance imaging (MRI), could elicit changes in the developing rat brain. Embryonic day 15 (E15) and postnatal day 14 (P14) rats were exposed to MRI using a 7.05 T MR system. The animals were anesthetized and exposed for 35 min per day for 4 successive days. Control animals were anesthetized but no MRI was performed. Body temperature was maintained at 37 o C. BrdU was injected after each session (50 mg/kg). One month later, cell proliferation, neurogenesis and astrogenesis in the dentate gyrus were evaluated, revealing no effects of MRI, neither in the E15, nor in the P14 group. DNA damage in the dentate gyrus in the P14 group was evaluated on P18, 1 day after the last session, using TUNEL staining. There was no difference in the number of TUNEL-positive cells after MRI compared with controls, neither in mature neurons, nor in newborn progenitors (BrdU/TUNEL double-labeled cells). Novel object recognition was performed to assess memory function 1 month after MRI. There was no difference in the recognition index observed after MRI compared with the control rats, neither for the E15, nor for the P14 group. In conclusion, repeated exposure to MRI did not appear to affect neurogenesis, cell death or memory function in rats, neither in late gestation (E15-E18) nor in young postnatal (P14-P17) rats.

Inducible Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis in the Olfactory Bulb and Improves Olfactory Function

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Wang, Wenbin; Lu, Song; Li, Tan; Pan, Yung-Wei; Zou, Junhui; Abel, Glen M.; Xu, Lihong; Storm, Daniel R.

2015-01-01

Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury. PMID:25995470

Amyloid β Is Not the Major Factor Accounting for Impaired Adult Hippocampal Neurogenesis in Mice Overexpressing Amyloid Precursor Protein

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Hongyu Pan

2016-10-01

Full Text Available Adult hippocampal neurogenesis was impaired in several Alzheimer's disease models overexpressing mutant human amyloid precursor protein (hAPP. However, the effects of wild-type hAPP on adult neurogenesis and whether the impaired adult hippocampal neurogenesis was caused by amyloid β (Aβ or APP remained unclear. Here, we found that neurogenesis was impaired in the dentate gyrus (DG of adult mice overexpressing wild-type hAPP (hAPP-I5 compared with controls. However, the adult hippocampal neurogenesis was more severely impaired in hAPP-I5 than that in hAPP-J20 mice, which express similar levels of hAPP mRNA but much higher levels of Aβ. Furthermore, reducing Aβ levels did not affect the number of doublecortin-positive cells in the DG of hAPP-J20 mice. Our results suggested that hAPP was more likely an important factor inhibiting adult neurogenesis, and Aβ was not the major factor affecting neurogenesis in the adult hippocampus of hAPP mice.

Delayed and transient increase of adult hippocampal neurogenesis by physical exercise in DBA/2 mice.

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Rupert W Overall

Full Text Available This study builds on the findings that physical activity, such as wheel running in mice, enhances cell proliferation and neurogenesis in the adult hippocampus of the common mouse strain C57BL/6, and that the baseline level of neurogenesis varies by strain, being considerably lower in DBA/2. Because C57BL/6 and DBA/2 are important as the parental strains of the BXD recombinant inbred cross which allows the detection of genetic loci regulating phenotypes such as adult neurogenesis, we performed the current study to investigate the gene x environment interactions regulating neurogenesis. At equal distances and times run DBA/2J mice lacked the acute increase in precursor cell proliferation known from C57BL/6. In DBA/2J proliferation even negatively correlated with the distance run. This was neither due to a stress response (to running itself or single housing nor differences in estrous cycle. DBA/2 animals exhibited a delayed and weaker pro-neurogenic response with a significant increase in numbers of proliferating cells first detectable after more than a week of wheel running. The proliferative response to running was transient in both strains, the effect being undetectable by 6 weeks. There was also a small transient increase in the production of new neurons in DBA/2J, although these extra cells did not survive. These findings indicate that the comparison between C57BL/6 and DBA/2, and by extension the BXD genetic reference population derived from these strains, should provide a powerful tool for uncovering the complex network of modifier genes affecting the activity-dependent regulation of adult hippocampal neurogenesis. More generally, our findings also describe how the external physical environment interacts with the internal genetic environment to produce different responses to the same behavioral stimuli.

Gradient biomaterials and their influences on cell migration

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Wu, Jindan; Mao, Zhengwei; Tan, Huaping; Han, Lulu; Ren, Tanchen; Gao, Changyou

2012-01-01

Cell migration participates in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. The cells specifically migrate to destiny sites induced by the gradually varying concentration (gradient) of soluble signal factors and the ligands bound with the extracellular matrix in the body during a wound healing process. Therefore, regulation of the cell migration behaviours is of paramount importance in regenerative medicine. One important way is to create a microenvironment that mimics the in vivo cellular and tissue complexity by incorporating physical, chemical and biological signal gradients into engineered biomaterials. In this review, the gradients existing in vivo and their influences on cell migration are briefly described. Recent developments in the fabrication of gradient biomaterials for controlling cellular behaviours, especially the cell migration, are summarized, highlighting the importance of the intrinsic driving mechanism for tissue regeneration and the design principle of complicated and advanced tissue regenerative materials. The potential uses of the gradient biomaterials in regenerative medicine are introduced. The current and future trends in gradient biomaterials and programmed cell migration in terms of the long-term goals of tissue regeneration are prospected. PMID:23741610

Detrimental role of prolonged sleep deprivation on adult neurogenesis

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Carina eFernandes

2015-04-01

Full Text Available Adult mammalian brains continuously generate new neurons, a phenomenon called neurogenesis. Both environmental stimuli and endogenous factors are important regulators of neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and neurogenesis in brain function, such as learning, memory and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on neurogenesis.

Collective cell migration: Implications for wound healing and cancer invasion

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Li Li

2013-07-01

Full Text Available During embryonic morphogenesis, wound repair and cancer invasion, cells often migrate collectively via tight cell-cell junctions, a process named collective migration. During such migration, cells move as coherent groups, large cell sheets, strands or tubes rather than individually. One unexpected finding regarding collective cell migration is that being a "multicellular structure" enables cells to better respond to chemical and physical cues, when compared with isolated cells. This is important because epithelial cells heal wounds via the migration of large sheets of cells with tight intercellular connections. Recent studies have gained some mechanistic insights that will benefit the clinical understanding of wound healing in general. In this review, we will briefly introduce the role of collective cell migration in wound healing, regeneration and cancer invasion and discuss its underlying mechanisms as well as implications for wound healing.

Adult neurogenesis supports short-term olfactory memory.

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Arenkiel, Benjamin R

2010-06-01

Adult neurogenesis has captivated neuroscientists for decades, with hopes that understanding the programs underlying this phenomenon may provide unique insight toward avenues for brain repair. Interestingly, however, despite intense molecular and cellular investigation, the evolutionary roles and biological functions for ongoing neurogenesis have remained elusive. Here I review recent work published in the Journal of Neuroscience that reveals a functional role for continued neurogenesis toward forming short-term olfactory memories.

3D cancer cell migration in a confined matrix

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Alobaidi, Amani; Sun, Bo

Cancer cell migration is widely studied in 2D motion, which does not mimic the invasion processes in vivo. More recently, 3D cell migration studies have been performed. The ability of cancer cells to migrate within the extracellular matrix depends on the physical and biochemical features of the extracellular matrix. We present a model of cell motility in confined matrix geometry. The aim of the study is to study cancer migration in collagen matrix, as a soft tissue, to investigate their motility within the confined and surrounding collagen environment. Different collagen concentrations have been used to show the ability of these cancer cells to move through such a complex structure by measuring Cancer cell migration velocity as well as the displacement. Graduate student physics department.

Impairments in neurogenesis are not tightly linked to depressive behavior in a transgenic mouse model of Alzheimer's disease.

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Daniel M Iascone

Full Text Available Alzheimer's disease (AD, the most common cause of dementia, is also associated with depression. Although the precise mechanisms that lead to depression in AD are unknown, the impairments in adult hippocampal neurogenesis observed in AD may play a role. Adult-born neurons play a critical role in regulating both cognition and mood, and reduced hippocampal neurogenesis is associated with depression in other neurological disorders. To assess the relationship between Alzheimer's disease, neurogenesis, and depression, we studied human amyloid precursor protein (hAPP transgenic mice, a well-characterized model of AD. We report that reductions in hippocampal neurogenesis are evident early in disease progression in hAPP mice, but a mild depressive phenotype manifests only in later stages of disease. We found that hAPP mice exhibited a reduction in BrdU-positive cells in the subgranular zone of the dentate gyrus in the hippocampus, as well as a reduction in doublecortin-expressing cells, relative to nontransgenic controls at 5-7 months of age. These alterations in neurogenesis appeared to worsen with age, as the magnitude of reduction in doublecortin-expressing cells was greater in hAPP mice at 13-15 months of age. Only 13-15 month old hAPP mice exhibited depressive behavior in the tail suspension test. However, mice at both age groups exhibited deficits in spatial memory, which was observed in the Morris water maze test for hippocampus-dependent memory. These findings indicate that neurogenesis impairments are accompanied by cognitive deficits, but are not tightly linked to depressive behavior in hAPP mice.

Learning-dependent neurogenesis in the olfactory bulb determines long-term olfactory memory.

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Sultan, S; Mandairon, N; Kermen, F; Garcia, S; Sacquet, J; Didier, A

2010-07-01

Inhibitory interneurons of the olfactory bulb are subjected to permanent adult neurogenesis. Their number is modulated by learning, suggesting that they could play a role in plastic changes of the bulbar network associated with olfactory memory. Adult male C57BL/6 mice were trained in an associative olfactory task, and we analyzed long-term retention of the task 5, 30, and 90 d post-training. In parallel, we assessed the fate of these newborn cells, mapped their distribution in the olfactory bulb and measured their functional implication using the immediate early gene Zif268. In a second set of experiments, we pharmacologically modulated glutamatergic transmission and using the same behavioral task assessed the consequences on memory retention and neurogenesis. Finally, by local infusion of an antimitotic drug, we selectively blocked neurogenesis during acquisition of the task and looked at the effects on memory retention. First we demonstrated that retrieval of an associative olfactory task recruits the newborn neurons in odor-specific areas of the olfactory bulb selected to survive during acquisition of the task and that it does this in a manner that depends on the strength of learning. We then demonstrated that acquisition is not dependent on neurogenesis if long-term retention of the task is abolished by blocking neurogenesis. Adult-born neurons are thus involved in changes in the neural representation of an odor; this underlies long-term olfactory memory as the strength of learning is linked to the duration of this memory. Neurogenesis thus plays a crucial role in long-term olfactory memory.

How Do Cells Make Decisions: Engineering Micro- and Nanoenvironments for Cell Migration

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Siti Hawa Ngalim

2010-01-01

Full Text Available Cell migration contributes to cancer metastasis and involves cell adhesion to the extracellular matrix (ECM, force generation through the cell's cytoskeletal, and finally cell detachment. Both adhesive cues from the ECM and soluble cues from neighbouring cells and tissue trigger intracellular signalling pathways that are essential for cell migration. While the machinery of many signalling pathways is relatively well understood, how hierarchies of different and conflicting signals are established is a new area of cellular cancer research. We examine the recent advances in microfabrication, microfluidics, and nanotechnology that can be utilized to engineer micro- and nanoscaled cellular environments. Controlling both adhesive and soluble cues for migration may allow us to decipher how cells become motile, choose the direction for migration, and how oncogenic transformations influences these decision-making processes.

Plectin deficiency in liver cancer cells promotes cell migration and sensitivity to sorafenib treatment.

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Cheng, Chiung-Chi; Chao, Wei-Ting; Liao, Chen-Chun; Tseng, Yu-Hui; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Hsu, Yung-Hsiang; Liu, Yi-Hsiang

2018-01-02

Plectin involved in activation of kinases in cell signaling pathway and plays important role in cell morphology and migration. Plectin knockdown promotes cell migration by activating focal adhesion kinase and Rac1-GTPase activity in liver cells. Sorafenib is a multi-targeting tyrosine kinase inhibitor that improves patient survival on hepatocellular carcinoma. The aim of this study is to investigate the correlation between the expression of plectin and cell migration as well as the sensitivity of hepatoma cell lines exposing to sorafenib. Hepatoma cell lines PLC/PRF/5 and HepG2 were used to examine the level of plectin expression and cell migration in comparison with Chang liver cell line. In addition, sensitivity of the 3 cell lines to sorafenib treatment was also measured. Expression of plectin was lower in PLC/PRF/5 and HepG2 hepatoma cells than that of Chang liver cells whereas HepG2 and PLC/PRF/5 cells exhibit higher rate of cell migration in trans-well migration assay. Immunohistofluorecent staining on E-cadherin revealed the highest rate of collective cell migration in HepG2 cells and the lowest was found in Chang liver cells. Likewise, HepG2 cell line was most sensitive to sorafenib treatment and Chang liver cells exhibited the least sensitivity. The drug sensitivity to sorafenib treatment showed inverse correlation with the expression of plectin. We suggest that plectin deficiency and increased E-cadherin in hepatoma cells were associated with higher rates of cell motility, collective cell migration as well as higher drug sensitivity to sorafenib treatment.

Interaction Effect of Social Isolation and High Dose Corticosteroid on Neurogenesis and Emotional Behavior.

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Chan, Jackie N-M; Lee, Jada C-D; Lee, Sylvia S P; Hui, Katy K Y; Chan, Alan H L; Fung, Timothy K-H; Sánchez-Vidaña, Dalinda I; Lau, Benson W-M; Ngai, Shirley P-C

2017-01-01

Hypercortisolemia is one of the clinical features found in depressed patients. This clinical feature has been mimicked in animal studies via application of exogenous corticosterone (CORT). Previous studies suggested that CORT can induce behavioral disturbance in anxious-depressive like behavior, which is associated with suppressed neurogenesis. Hippocampal neurogenesis plays an important role in adult cognitive and behavioral regulation. Its suppression may thus lead to neuropsychiatric disorders. Similar to the effects of CORT on the animals' depression-like behaviors and neurogenesis, social deprivation has been regarded as one factor that predicts poor prognosis in depression. Furthermore, social isolation is regarded as a stressor to social animals including experimental rodents. Hence, this study aims to examine if social isolation would induce further emotional or anxiety-like behavior disturbance and suppress neurogenesis in an experimental model that was repeatedly treated with CORT. Sprague-Dawley rats were used in this study to determine the effects of different housing conditions, either social isolated or group housing, in vehicle-treated control and CORT-treated animals. Forced swimming test (FST), open field test (OFT) and social interaction test (SIT) were used to assess depression-like, anxiety-like and social behaviors respectively. Immunohistochemistry was performed to quantify the number of proliferative cells and immature neurons in the hippocampus, while dendritic maturation of immature neurons was analyzed by Sholl analysis. Social isolation reduced latency to immobility in FST. Furthermore, social isolation could significantly reduce the ratio of doublecortin and bromodeoxyuridine (BrdU) positive cells of the neurogenesis assay under CORT-treated condition. The current findings suggested that the behavioral and neurological effect of social isolation is dependent on the condition of hypercortisolemia. Furthermore, social isolation may

Src Induces Podoplanin Expression to Promote Cell Migration*

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Shen, Yongquan; Chen, Chen-Shan; Ichikawa, Hitoshi; Goldberg, Gary S.

2010-01-01

Nontransformed cells can force tumor cells to assume a normal morphology and phenotype by the process of contact normalization. Transformed cells must escape this process to become invasive and malignant. However, mechanisms underlying contact normalization have not been elucidated. Here, we have identified genes that are affected by contact normalization of Src-transformed cells. Tumor cells must migrate to become invasive and malignant. Src must phosphorylate the adaptor protein Cas (Crk-associated substrate) to promote tumor cell motility. We report here that Src utilizes Cas to induce podoplanin (Pdpn) expression to promote tumor cell migration. Pdpn is a membrane-bound extracellular glycoprotein that associates with endogenous ligands to promote tumor cell migration leading to cancer invasion and metastasis. In fact, Pdpn expression accounted for a major part of the increased migration seen in Src-transformed cells. Moreover, nontransformed cells suppressed Pdpn expression in adjacent Src-transformed cells. Of >39,000 genes, Pdpn was one of only 23 genes found to be induced by transforming Src activity and suppressed by contact normalization of Src-transformed cells. In addition, we found 16 genes suppressed by Src and induced by contact normalization. These genes encode growth factor receptors, adaptor proteins, and products that have not yet been annotated and may play important roles in tumor cell growth and migration. PMID:20123990

Third harmonic generation imaging of intact human cerebral organoids to assess key components of early neurogenesis in Rett Syndrome (Conference Presentation)

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Yildirim, Murat; Feldman, Danielle; Wang, Tianyu; Ouzounov, Dimitre G.; Chou, Stephanie; Swaney, Justin; Chung, Kwanghun; Xu, Chris; So, Peter T. C.; Sur, Mriganka

2017-02-01

Rett Syndrome (RTT) is a pervasive, X-linked neurodevelopmental disorder that predominantly affects girls. It is mostly caused by a sporadic mutation in the gene encoding methyl CpG-binding protein 2 (MeCP2).The clinical features of RTT are most commonly reported to emerge between the ages of 6-18 months and implicating RTT as a disorder of postnatal development. However, a variety of recent evidence from our lab and others demonstrates that RTT phenotypes are present at the earliest stages of brain development including neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. We have used RTT patient-derived induced pluripotent stem cells to generate 3D human cerebral organoids that can serve as a model for human neurogenesis in vitro. We aim to expand on our existing findings in order to determine aberrancies at individual stages of neurogenesis by performing structural and immunocytochemical staining in isogenic control and MeCP2-deficient organoids. In addition, we aim to use Third Harmonic Generation (THG) microscopy as a label-free, nondestructive 3D tissue visualization method in order to gain a complete understanding of the structural complexity that underlies human neurogenesis. As a proof of concept, we have performed THG imaging in healthy intact human cerebral organoids cleared with SWITCH. We acquired an intrinsic THG signal with the following laser configurations: 400 kHz repetition rate, 65 fs pulse width laser at 1350 nm wavelength. In these THG images, nuclei are clearly delineated and cross sections demonstrate the depth penetration capacity (< 1mm) that extends throughout the organoid. Imaging control and MeCP2-deficient human cerebral organoids in 2D sections reveals structural and protein expression-based alterations that we expect will be clearly elucidated via both THG and three-photon fluorescence microscopy.

Directional Cell Migration in Response to Repeated Substratum Stretching

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Okimura, Chika; Iwadate, Yoshiaki

2017-10-01

Crawling migration plays an essential role in a variety of biological phenomena, including development, wound healing, and immune system function. Migration properties such as anterior-posterior polarity, directionality, and velocity are regulated not only by the reception of a chemoattractant but also by sensing mechanical inputs from the external environment. In this review, we describe the mechanical response of migrating cells, particularly under repeated stretching of the elastic substratum, highlighting the fact that there appear to be two independent mechanosensing systems that generate the polarity needed for migration. Cells that have no stress fibers, such as Dictyostelium cells and neutrophil-like differentiated HL-60 cells, migrate perpendicular to the stretching direction via myosin II localization. Cells that do possess stress fibers, however, such as fish keratocytes, migrate parallel to the stretching via a stress-fiber-dependent process.

Regulation of neurogenesis: factors affecting of new neurons formation in adult mammals brain

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Michalina Respondek

2015-12-01

Full Text Available Neurogenesis is a complex and multi-step process of generating completely functional neurons. This process in adult brain is based on pluripotentional neuronal stem cells (NSC, which are able to proliferation and differentiation into mature neurons or glial cells. NSC are located in subgranular zone inside hippocampus and in subventricular zone. The new neurons formation depends on many endo- and exogenous factors which modulate each step of neurogenesis. This article describes the most important regulators of adult neurogenesis, mainly: neurotrophins, growth factors, hormones, neurotransmitters and microenvironment of NSC. Some drugs, especially antipsychotics, antidepressants and normothymics may affect the neurogenic properties of adult brain. Moreover pathological processes such as neuroinflammation, stroke or epilepsy are able to induce proliferation of NSC. The proneurogenic effects of psychotropic drugs and pathological processes are associated with their ability to increase some hormones and neurotrophins level, as well as with rising the expression of antiapoptotic Bcl-2 protein and metalloproteinase MMP-2. Additionaly, some drugs, for example haloperidol, are able to block prolactin and dopaminergic neuroblasts receptors. Down-regulation of adult neurogenesis is associated with alcohol abuse and high stress level. Negative effect of many drugs, such as cytostatics, COX-2 inhibitors and opioides was also observed. The proneurogenic effect of described factors suggest their broad therapeutic potential and gives a new perspective on an effective and modern treatment of many neuropsychiatric disorders. This effect can also help to clarify the pathogenesis of disorders associated with proliferation and degeneration of adult brain cells.

PMC-12, a traditional herbal medicine, enhances learning memory and hippocampal neurogenesis in mice.

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Park, Hee Ra; Kim, Ju Yeon; Lee, Yujeong; Chun, Hye Jeong; Choi, Young Whan; Shin, Hwa Kyoung; Choi, Byung Tae; Kim, Cheol Min; Lee, Jaewon

2016-03-23

The beneficial effects of traditional Korean medicine are recognized during the treatment of neurodegenerative conditions, such as, Alzheimer's disease and neurocognitive dysfunction, and recently, hippocampal neurogenesis has been reported to be associated with memory function. In this study, the authors investigated the beneficial effects of polygonum multiflorum Thunberg complex composition-12 (PMC-12), which is a mixture of four medicinal herbs, that is, Polygonum multiflorum, Polygala tenuifolia, Rehmannia glutinosa, and Acorus gramineus, on hippocampal neurogenesis, learning, and memory in mice. PMC-12 was orally administered to male C57BL/6 mice (5 weeks old) at 100 or 500 mg/kg daily for 2 weeks. PMC-12 administration significantly was found to increase the proliferation of neural progenitor cells and the survival of newly-generated cells in the dentate gyrus. In the Morris water maze test, the latency times of PMC-12 treated mice (100 or 500 mg/kg) were shorter than those of vehicle-control mice. In addition, PMC-12 increased the levels of BDNF, p-CREB, and synaptophysin, which are known to be associated with neural plasticity and hippocampal neurogenesis. These findings suggest PMC-12 enhances hippocampal neurogenesis and neurocognitive function and imply that PMC-12 ameliorates memory impairment and cognitive deficits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Proteomic analysis of astrocytic secretion that regulates neurogenesis using quantitative amine-specific isobaric tagging

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Yan, Hu; Zhou, Wenhao [Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Wei, Liming; Zhong, Fan [Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Roda, Shanghai 200032 (China); Yang, Yi, E-mail: yyang@shmu.edu.cn [Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China)

2010-01-08

Astrocytes are essential components of neurogenic niches that affect neurogenesis through membrane association and/or the release of soluble factors. To identify factors released from astrocytes that could regulate neural stem cell differentiation and proliferation, we used mild oxygen-glucose deprivation (OGD) to inhibit the secretory capacity of astrocytes. Using the Transwell co-culture system, we found that OGD-treated astrocytes could not promote neural stem cell differentiation and proliferation. Next, isobaric tagging for the relative and absolute quantitation (iTRAQ) proteomics techniques was performed to identify the proteins in the supernatants of astrocytes (with or without OGD). Through a multi-step analysis and gene ontology classification, 130 extracellular proteins were identified, most of which were involved in neuronal development, the inflammatory response, extracellular matrix composition and supportive functions. Of these proteins, 44 had never been reported to be produced by astrocytes. Using ProteinPilot software analysis, we found that 60 extracellular proteins were significantly altered (27 upregulated and 33 downregulated) in the supernatant of OGD-treated astrocytes. Among these proteins, 7 have been reported to be able to regulate neurogenesis, while others may have the potential to regulate neurogenesis. This study profiles the major proteins released by astrocytes, which play important roles in the modulation of neurogenesis.

Proteomic analysis of astrocytic secretion that regulates neurogenesis using quantitative amine-specific isobaric tagging

International Nuclear Information System (INIS)

Yan, Hu; Zhou, Wenhao; Wei, Liming; Zhong, Fan; Yang, Yi

2010-01-01

Astrocytes are essential components of neurogenic niches that affect neurogenesis through membrane association and/or the release of soluble factors. To identify factors released from astrocytes that could regulate neural stem cell differentiation and proliferation, we used mild oxygen-glucose deprivation (OGD) to inhibit the secretory capacity of astrocytes. Using the Transwell co-culture system, we found that OGD-treated astrocytes could not promote neural stem cell differentiation and proliferation. Next, isobaric tagging for the relative and absolute quantitation (iTRAQ) proteomics techniques was performed to identify the proteins in the supernatants of astrocytes (with or without OGD). Through a multi-step analysis and gene ontology classification, 130 extracellular proteins were identified, most of which were involved in neuronal development, the inflammatory response, extracellular matrix composition and supportive functions. Of these proteins, 44 had never been reported to be produced by astrocytes. Using ProteinPilot software analysis, we found that 60 extracellular proteins were significantly altered (27 upregulated and 33 downregulated) in the supernatant of OGD-treated astrocytes. Among these proteins, 7 have been reported to be able to regulate neurogenesis, while others may have the potential to regulate neurogenesis. This study profiles the major proteins released by astrocytes, which play important roles in the modulation of neurogenesis.

Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

Science.gov (United States)

Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

2015-01-01

Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.

Collective cell migration drives morphogenesis of the kidney nephron.

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Aleksandr Vasilyev

2009-01-01

Full Text Available Tissue organization in epithelial organs is achieved during development by the combined processes of cell differentiation and morphogenetic cell movements. In the kidney, the nephron is the functional organ unit. Each nephron is an epithelial tubule that is subdivided into discrete segments with specific transport functions. Little is known about how nephron segments are defined or how segments acquire their distinctive morphology and cell shape. Using live, in vivo cell imaging of the forming zebrafish pronephric nephron, we found that the migration of fully differentiated epithelial cells accounts for both the final position of nephron segment boundaries and the characteristic convolution of the proximal tubule. Pronephric cells maintain adherens junctions and polarized apical brush border membranes while they migrate collectively. Individual tubule cells exhibit basal membrane protrusions in the direction of movement and appear to establish transient, phosphorylated Focal Adhesion Kinase-positive adhesions to the basement membrane. Cell migration continued in the presence of camptothecin, indicating that cell division does not drive migration. Lengthening of the nephron was, however, accompanied by an increase in tubule cell number, specifically in the most distal, ret1-positive nephron segment. The initiation of cell migration coincided with the onset of fluid flow in the pronephros. Complete blockade of pronephric fluid flow prevented cell migration and proximal nephron convolution. Selective blockade of proximal, filtration-driven fluid flow shifted the position of tubule convolution distally and revealed a role for cilia-driven fluid flow in persistent migration of distal nephron cells. We conclude that nephron morphogenesis is driven by fluid flow-dependent, collective epithelial cell migration within the confines of the tubule basement membrane. Our results establish intimate links between nephron function, fluid flow, and morphogenesis.

Plasticity of cell migration: a multiscale tuning model.

NARCIS (Netherlands)

Friedl, P.H.A.; Wolf, K. van der

2010-01-01

Cell migration underlies tissue formation, maintenance, and regeneration as well as pathological conditions such as cancer invasion. Structural and molecular determinants of both tissue environment and cell behavior define whether cells migrate individually (through amoeboid or mesenchymal modes) or

Oligodendrogenesis and neurogenesis in remyelination in the cuprizone model of multiple sclerosis: correlation with the degree of lesion

Science.gov (United States)

Pishchelko, A.; Khodanovich, M.; Pan, E.; Glazacheva, V.; Akulov, A.; Yarnykh, V.

2017-08-01

In this research, a cuprizone model of multiple sclerosis (MS) was used to study oligodendrogenesis and neurogenesis in remyelination. It has been shown that, with the administration of cuprizone, the amount of myelin in a number of structures of white and gray matter and the level of neurogenesis decrease, while the level of oligodendrogenesis increases. The withdrawal of cuprizone leads to the restoration of myelin content, the reduction of the excessive production of oligodendrocytes and to the restoration of the number of neurons to control values. The negative correlation between the number of oligodendrocyte precursors (OPCs) and the degree of demyelination of the corpus callosum indicates migration of OLG precursors from the subventricular zone (SVZ) to the structure during demyelination.

Follow-the-leader cell migration requires biased cell–cell contact and local microenvironmental signals

International Nuclear Information System (INIS)

Wynn, Michelle L; Rupp, Paul; Trainor, Paul A; Kulesa, Paul M; Schnell, Santiago

2013-01-01

Directed cell migration often involves at least two types of cell motility that include multicellular streaming and chain migration. However, what is unclear is how cell contact dynamics and the distinct microenvironments through which cells travel influence the selection of one migratory mode or the other. The embryonic and highly invasive neural crest (NC) are an excellent model system to study this question since NC cells have been observed in vivo to display both of these types of cell motility. Here, we present data from tissue transplantation experiments in chick and in silico modeling that test our hypothesis that cell contact dynamics with each other and the microenvironment promote and sustain either multicellular stream or chain migration. We show that when premigratory cranial NC cells (at the pre-otic level) are transplanted into a more caudal region in the head (at the post-otic level), cells alter their characteristic stream behavior and migrate in chains. Similarly, post-otic NC cells migrate in streams after transplantation into the pre-otic hindbrain, suggesting that local microenvironmental signals dictate the mode of NC cell migration. Simulations of an agent-based model (ABM) that integrates the NC cell behavioral data predict that chain migration critically depends on the interplay of biased cell–cell contact and local microenvironment signals. Together, this integrated modeling and experimental approach suggests new experiments and offers a powerful tool to examine mechanisms that underlie complex cell migration patterns. (paper)

Interleukin-1β: A New Regulator of the Kynurenine Pathway Affecting Human Hippocampal Neurogenesis

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Zunszain, Patricia A; Anacker, Christoph; Cattaneo, Annamaria; Choudhury, Shanas; Musaelyan, Ksenia; Myint, Aye Mu; Thuret, Sandrine; Price, Jack; Pariante, Carmine M

2012-01-01

Increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. Here, we show for the first time how IL-1β, a pro-inflammatory cytokine shown to be increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. IL-1β was detrimental to neurogenesis, as shown by a decrease in the number of doublecortin-positive neuroblasts (−28%), and mature, microtubule-associated protein-2-positive neurons (−36%). Analysis of the enzymes that regulate the kynurenine pathway showed that IL-1β induced an upregulation of transcripts for indolamine-2,3-dioxygenase (IDO), kynurenine 3-monooxygenase (KMO), and kynureninase (42-, 12- and 30-fold increase, respectively, under differentiating conditions), the enzymes involved in the neurotoxic arm of the kynurenine pathway. Moreover, treatment with IL-1β resulted in an increase in kynurenine, the catabolic product of IDO-induced tryptophan metabolism. Interestingly, co-treatment with the KMO inhibitor Ro 61-8048 reversed the detrimental effects of IL-1β on neurogenesis. These observations indicate that IL-1β has a critical role in regulating neurogenesis whereas affecting the availability of tryptophan and the production of enzymes conducive to toxic metabolites. Our results suggest that inhibition of the kynurenine pathway may provide a new therapy to revert inflammatory-induced reduction in neurogenesis. PMID:22071871

Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function.

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Wang, Wenbin; Lu, Song; Li, Tan; Pan, Yung-Wei; Zou, Junhui; Abel, Glen M; Xu, Lihong; Storm, Daniel R; Xia, Zhengui

2015-05-20

Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury. Copyright © 2015 the authors 0270-6474/15/357833-17$15.00/0.

Is forebrain neurogenesis a potential repair mechanism after stroke?

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Inta, Dragos; Gass, Peter

2015-01-01

The use of adult subventricular zone (SVZ) neurogenesis as brain repair strategy after stroke represents a hot topic in neurologic research. Recent radiocarbon-14 dating has revealed a lack of poststroke neurogenesis in the adult human neocortex; however, adult neurogenesis has been shown to occur, even under physiologic conditions, in the human striatum. Here, these results are contrasted with experimental poststroke neurogenesis in the murine brain. Both in humans and in rodents, the SVZ ge...

Silk Film Topography Directs Collective Epithelial Cell Migration

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Rosenblatt, Mark I.

2012-01-01

The following study provides new insight into how surface topography dictates directed collective epithelial cell sheet growth through the guidance of individual cell movement. Collective cell behavior of migrating human corneal limbal-epithelial cell sheets were studied on highly biocompatible flat and micro-patterned silk film surfaces. The silk film edge topography guided the migratory direction of individual cells making up the collective epithelial sheet, which resulted in a 75% increase in total culture elongation. This was due to a 3-fold decrease in cell sheet migration rate efficiency for movement perpendicular to the topography edge. Individual cell migration direction is preferred in the parallel approach to the edge topography where localization of cytoskeletal proteins to the topography’s edge region is reduced, which results in the directed growth of the collective epithelial sheet. Findings indicate customized biomaterial surfaces may be created to direct both the migration rate and direction of tissue epithelialization. PMID:23185573

Characteristics of meniscus progenitor cells migrated from injured meniscus.

Science.gov (United States)

Seol, Dongrim; Zhou, Cheng; Brouillette, Marc J; Song, Ino; Yu, Yin; Choe, Hyeong Hun; Lehman, Abigail D; Jang, Kee W; Fredericks, Douglas C; Laughlin, Barbara J; Martin, James A

2017-09-01

Serious meniscus injuries seldom heal and increase the risk for knee osteoarthritis; thus, there is a need to develop new reparative therapies. In that regard, stimulating tissue regeneration by autologous stem/progenitor cells has emerged as a promising new strategy. We showed previously that migratory chondrogenic progenitor cells (CPCs) were recruited to injured cartilage, where they showed a capability in situ tissue repair. Here, we tested the hypothesis that the meniscus contains a similar population of regenerative cells. Explant studies revealed that migrating cells were mainly confined to the red zone in normal menisci: However, these cells were capable of repopulating defects made in the white zone. In vivo, migrating cell numbers increased dramatically in damaged meniscus. Relative to non-migrating meniscus cells, migrating cells were more clonogenic, overexpressed progenitor cell markers, and included a larger side population. Gene expression profiling showed that the migrating population was more similar to CPCs than other meniscus cells. Finally, migrating cells equaled CPCs in chondrogenic potential, indicating a capacity for repair of the cartilaginous white zone of the meniscus. These findings demonstrate that, much as in articular cartilage, injuries to the meniscus mobilize an intrinsic progenitor cell population with strong reparative potential. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1966-1972, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease

International Nuclear Information System (INIS)

Tang, Jun; Song, Min; Wang, Yanyan; Fan, Xiaotang; Xu, Haiwei; Bai, Yun

2009-01-01

In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP swe /PS1 ΔE9 mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP swe /PS1 ΔE9 transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

Effects of TNF-alpha on Endothelial Cell Collective Migration

Science.gov (United States)

Chen, Desu; Wu, Di; Helim Aranda-Espinoza, Jose; Losert, Wolfgang

2013-03-01

Tumor necrosis factor (TNF-alpha) is a small cell-signaling protein usually released by monocytes and macrophages during an inflammatory response. Previous work had shown the effects of TNF-alpha on single cell morphology, migration, and biomechanical properties. However, the effect on collective migrations remains unexplored. In this work, we have created scratches on monolayers of human umbilical endothelial cells (HUVECs) treated with 25ng/mL TNF-alpha on glass substrates. The wound healing like processes were imaged with phase contrast microscopy. Quantitative analysis of the collective migration of cells treated with TNF-alpha indicates that these cells maintain their persistent motion and alignment better than untreated cells. In addition, the collective migration was characterized by measuring the amount of non-affine deformations of the wound healing monolayer. We found a lower mean non-affinity and narrower distribution of non-affinities upon TNF-alpha stimulation. These results suggest that TNF-alpha introduces a higher degree of organized cell collective migration.

Neurogenesis in the brain stem of the rabbit: an autoradiographic study

International Nuclear Information System (INIS)

Oblinger, M.M.; Das, G.D.

1981-01-01

With the aid of ( 3 H)-thymidine autoradiography, neurogenesis was documented in the nuclear groups of the medulla oblongata, pons, and mid-brain, as well as in the brain stem reticular formation of the rabbit. Following single injections of ( 3 H)-thymidine, counts were taken of intensely labeled neurons within the nuclei of the functional columns related to the cranial nerves, nuclei of several other functional classifications, and nuclei that did not fit into a functional category. In the brain stem as a whole, neurogenesis was found to occur between days 10.0 and 18.5 of gestation: however, the majority of nuclei studied contained intensely neurons only between days 12.0 and 15.0. Only in the pontine nucleus and the tectum were intensely labeled cells observed as late as day 18.5. Directional gradients of histogenesis were often observed within, as well as between, various nuclei. Within the nuclear columns related to the cranial nerves, a clear mediolateral spread of neurogenesis was observable such that nuclei of the motor columns reached a peak in neurogenesis before those in the sensory columns. Likewise, a mediolateral proliferation pattern was seen in the brain stem reticular formation. Other individual directional gradients were discernible; however, in the brain stem as a whole, distinct overall gradients were not observable. In many individual nuclei, gradients in neuron size were observed such that large neurons preferentially arose prior to smaller neurons. Information pertaining to gradients in neurogenesis, as well as to relationships among functionally related nuclei, are discussed

Basics elements for modelling the dynamics of cell migration in cell culture

International Nuclear Information System (INIS)

FarIas, Ro; Vidal, Cs; Rapacioli, M; Flores, V

2007-01-01

This paper introduces some basic elements for modelling the dynamics of cell migration activity over a bi-dimensional substratum. A square matrix, representing the substratum, is implemented in order to generate virtual cells with an initial random uniform distribution, with the ability to freely move within the matrix and to interact with each others by mean of adhesive forces. Two different conditions were examined: A) cells can freely move and after contacting with another cell they both completely inhibit their migration; B) cells that come into contact have the ability to rotate respect to each other without losing their contacts and retaining the ability to move together but at a slower rate, being the decrease in the rate of movement proportional to the number of contacting cells. The dynamics of the migration process in these two conditions was evaluated by recording the evolution of several parameters as a function of time. Minor modifications in some parameters (mobility, intensity of cell-cell and cell-substratum adhesiveness) significantly change the dynamics and the final result of the virtual migrating cells

Specific radiosensitivy and postnatal neurogenesis of the dentate gyrus of rabbits

International Nuclear Information System (INIS)

Gueneau, Gerard.

1982-09-01

Adult and young rabbits were delivered a gamma exposure of 4.5 Gy. A light and electron microscope cytological investigation of the hippocampal region in the early hours following the exposure showed the particular radiosensitivity of the dentate gyrus which was demonstrated by: 1) pycnotic cells to be found at the basis of the granular cell layer (subgranular zone) exclusively; 2) a more discrete injury of the granular layer where most nuclei showed a lighter chromatin appearing as ''light spots''. Both radioinduced injuries are described, especially their kinetics, importance, and the effects of dose and age of the animal. The presence of pycnotic cells in the subgranular zone was related to the late postnatal neurogenesis occurring in this zone. The pattern and chronology of this late postnatal neurogenesis was investigated by autoradiography following 3 H thymidine injection. Finally, two series of investigations combining autoradiography and irradiation brought further data on the radiosensitivity and radioresistance of the dental gyrus cells and demonstrated the recovery capacity of the subgranular zone [fr

Automated migration analysis based on cell texture: method & reliability

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Chittenden Thomas W

2005-03-01

Full Text Available Abstract Background In this paper, we present and validate a way to measure automatically the extent of cell migration based on automated examination of a series of digital photographs. It was designed specifically to identify the impact of Second Hand Smoke (SHS on endothelial cell migration but has broader applications. The analysis has two stages: (1 preprocessing of image texture, and (2 migration analysis. Results The output is a graphic overlay that indicates the front lines of cell migration superimposed on each original image, with automated reporting of the distance traversed vs. time. Expert preference compares to manual placement of leading edge shows complete equivalence of automated vs. manual leading edge definition for cell migration measurement. Conclusion Our method is indistinguishable from careful manual determinations of cell front lines, with the advantages of full automation, objectivity, and speed.

ASIC proteins regulate smooth muscle cell migration.

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Grifoni, Samira C; Jernigan, Nikki L; Hamilton, Gina; Drummond, Heather A

2008-03-01

The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated that Epithelial Na(+)Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration; however, the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence individual ASIC expression and determine the importance of ASIC proteins in wound healing and chemotaxis (PDGF-bb)-initiated migration. We found ASIC1, ASIC2, and ASIC3, but not ASIC4, expression in A10 cells. ASIC1, ASIC2, and ASIC3 siRNA molecules significantly suppressed expression of their respective proteins compared to non-targeting siRNA (RISC) transfected controls by 63%, 44%, and 55%, respectively. Wound healing was inhibited by 10, 20, and 26% compared to RISC controls following suppression of ASIC1, ASIC2, and ASIC3, respectively. Chemotactic migration was inhibited by 30% and 45%, respectively, following suppression of ASIC1 and ASIC3. ASIC2 suppression produced a small, but significant, increase in chemotactic migration (4%). Our data indicate that ASIC expression is required for normal migration and may suggest a novel role for ASIC proteins in cellular migration.

ERK-dependent and -independent pathways trigger human neural progenitor cell migration

International Nuclear Information System (INIS)

Moors, Michaela; Cline, Jason E.; Abel, Josef; Fritsche, Ellen

2007-01-01

Besides differentiation and apoptosis, cell migration is a basic process in brain development in which neural cells migrate several centimeters within the developing brain before reaching their proper positions and forming the right connections. For identifying signaling events that control neural migration and are therefore potential targets of chemicals to disturb normal brain development, we developed a human neurosphere-based migration assay based on normal human neural progenitor (NHNP) cells, in which the distance is measured that cells wander over time. Applying this assay, we investigated the role of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the regulation of NHNP cell migration. Exposure to model substances like ethanol or phorbol 12-myristate 13-acetate (PMA) revealed a correlation between ERK1/2 activation and cell migration. The participation of phospho-(P-) ERK1/2 was confirmed by exposure of the cells to the MEK inhibitor PD98059, which directly prohibits ERK1/2 phosphorylation and inhibited cell migration. We identified protein kinase C (PKC) and epidermal growth factor receptor (EGFR) as upstream signaling kinases governing ERK1/2 activation, thereby controlling NHNP cell migration. Additionally, treatments with src kinase inhibitors led to a diminished cell migration without affecting ERK1/2 phosphorylation. Based on these results, we postulate that migration of NHNP cells is controlled via ERK1/2-dependent and -independent pathways

Cell-surface proteoglycan in sea urchin primary mesenchyme cell migration

International Nuclear Information System (INIS)

Lane, M.C.

1989-01-01

Early in the development of the sea urchin embryo, the primary mesenchyme cells (PMC) migrate along the basal lamina of the blastocoel. Migration is inhibited in L. pictus embryos cultured in sulfate-free seawater and in S. purpuratus embryos exposed to exogenous β-D-xylosides. An in vitro assay was developed to test the migratory capacity of normal PMC on normal and treated blastocoelic matrix. Sulfate deprivation and exposure to exogenous xyloside render PMC nonmotile on either matrix. Materials removed from the surface of normal PMC by treatment with 1 M urea restored migratory ability to defective cells, whereas a similar preparation isolated from the surface of epithelial cells at the same stage did not. Migration also resumed when cells were removed from the xyloside or returned to normal seawater. The urea extract was partially purified and characterized by radiolabeling, gel electrophoresis, fluorography, ion exchange chromatography, and western blotting. The PMC synthesize a large chondroitin sulfate/dermatan sulfate proteoglycan that is present in an active fraction isolated by chromatography. Chondroitinase ABC digestion of live cells blocked migration reversibly, further supporting the identification of the chondroitin sulfate/dermatan sulfate proteoglycan as the active component in the urea extract. Much of the incorporated sulfate was distributed along the filopodia in 35 SO 4 -labelled PMC by autoradiography. The morphology of normal and treated S. purpuratus PMC was examined by scanning electron microscopy, and differences in spreading, particularly of the extensive filopodia present on the cells, was observed. A model for the role of the chondroitin sulfate/dermatan sulfate proteoglycan in cell detachment during migration is proposed

Linking adult olfactory neurogenesis to social behavior

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Claudia E Feierstein

2012-11-01

Full Text Available In the adult brain, new neurons are added to two brain areas: the olfactory bulb and the hippocampus. Newly-generated neurons integrate into the preexisting circuits, bringing a set of unique properties, such as increased plasticity and responsiveness to stimuli. However, the functional implications of the constant addition of these neurons remain unclear, although they are believed to be important for learning and memory. The levels of neurogenesis are regulated by a variety of environmental factors, as well as during learning, suggesting that new neurons could be important for coping with changing environmental demands. Notably, neurogenesis has been shown to be physiologically regulated in relation to reproductive behavior: neurogenesis increases in female mice upon exposure to cues of the mating partners, during pregnancy and lactation, and in male mice upon exposure to their offspring. In this scenario, and because of the key contribution of olfaction to maternal behavior, we sought to investigate the contribution of adult-generated neurons in the olfactory system to maternal behavior and offspring recognition. To do so, we selectively disrupted neurogenesis in the olfactory pathway of female mice using focal irradiation. Disruption of adult neurogenesis in the olfactory bulb did not affect maternal behavior, or the ability of female mice to discriminate familiar from unfamiliar pups. However, reduction of olfactory neurogenesis resulted in abnormal social interaction of female mice, specifically with male conspecifics. Because the olfactory system is crucial for sex recognition, we suggest that the abnormal interaction with males could result from the inability to detect or discriminate male-specific odors and could therefore have implications for the recognition of potential mating partners. Here, I review the results of this and other studies, and discuss their implications for our understanding of the function of adult neurogenesis.

Defensive behaviors and prosencephalic neurogenesis in pigeons (Columba livia) are affected by environmental enrichment in adulthood.

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Melleu, F F; Pinheiro, M V; Lino-de-Oliveira, C; Marino-Neto, J

2016-05-01

Neurogenesis in the adult brain appears to be phylogenetically conserved across the animal kingdom. In pigeons and other adult non-oscine birds, immature neurons are observed in several prosencephalic areas, suggesting that neurogenesis may participate in the control of different behaviors. The mechanisms controlling neurogenesis and its relevance to defensive behaviors in non-oscine birds remain elusive. Herein, the contribution of the environment to behavior and neurogenesis of pigeons was investigated. Adult pigeons (Columba livia, n = 6/group), housed in standard (SE) or enriched environment (EE) for 42 days, were exposed to an unfamiliar environment (UE) followed by presentation to a novel object (NO). Video recordings of UE+NO tests were analyzed and scored for latency, duration and frequency of angular head movements, peeping, grooming, immobility and locomotion. Twenty-four hours later, pigeons were submitted to the tonic immobility test (TI) and number of trials for TI and TI duration were scored, followed by euthanasia 2 h later. Brains were immunohistochemically processed to reveal doublecortin (DCX), a marker for newborn neurons. Compared to those housed in SE, the pigeons housed in EE responded to a NO with more immobility. In addition, the pigeons housed in EE presented longer TI, more DCX-immunoreactive (DCX-ir) cells in the hippocampus and fewer DCX-ir cells in the lateral striatum than those housed in SE. There was no correlation between the number of DCX-ir cells and the scores of immobility in behavioral tests. Together, these data suggest that enrichment favored behavioral inhibition and neurogenesis in the adult pigeons through different, parallel mechanisms.

Female mice lacking cholecystokinin 1 receptors have compromised neurogenesis, and fewer dopaminergic cells in the olfactory bulb

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Yi eSui

2013-03-01

Full Text Available Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ of the lateral ventricle and subgranular zone (SGZ of the dentate gyrus (DG. We examined whether cholecystokinin (CCK through actions mediated by CCK1 receptors (CCK1R is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 37% and 42%, respectively, in female (but not male mice lacking CCK1Rs (CCK1R-/- compared to wild-type (WT. Generation of neuroblasts in the SVZ and rostral migratory stream was also affected, since the number of doublecortin (DCX-immunoreactive (ir neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R-/- mice, BrdU-positive (+ and Ki67-ir cells were reduced by 38% and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R-/- mice was examined. In the OB granule cell layer (GCL, the number of neuronal nuclei (NeuN-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI was similar. Compared to WT, the granule cell layer of the DG in female CCK1R-/- mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL of CCK1R-/- female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is

Central proliferation and neurogenesis is impaired in type 2 diabetes and prediabetes animal models.

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Juan Jose Ramos-Rodriguez

Full Text Available Type 2 diabetes (T2D is an important risk factor to suffer dementia, including Alzheimer's disease (AD, and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS morphological alterations in the db/db mice (leptin receptor KO mice, as a model of long-term insulin resistance and T2D, and in C57Bl6 mice fed with high fat diet (HFD, as a model of diet induced insulin resistance and prediabetes. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. We also detected increased neurogenesis and cell proliferation rates in young db/db mice when compared with control littermates. Our study shows that metabolic parameters serve as predictors of both atrophy and altered proliferation and neurogenesis in the CNS. Moreover in the cortex, atrophy, cell proliferation and neurogenesis were significantly correlated. Our data suggest that T2D may underline some of the pathological features observed in the dementia process. They also support that blood glucose control in elderly patients could help to slow down dementia evolution and maybe, improve its prognosis.

Increased radial glia quiescence, decreased reactivation upon injury and unaltered neuroblast behavior underlie decreased neurogenesis in the aging zebrafish telencephalon.

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Edelmann, Kathrin; Glashauser, Lena; Sprungala, Susanne; Hesl, Birgit; Fritschle, Maike; Ninkovic, Jovica; Godinho, Leanne; Chapouton, Prisca

2013-09-01

The zebrafish has recently become a source of new data on the mechanisms of neural stem cell (NSC) maintenance and ongoing neurogenesis in adult brains. In this vertebrate, neurogenesis occurs at high levels in all ventricular regions of the brain, and brain injuries recover successfully, owing to the recruitment of radial glia, which function as NSCs. This new vertebrate model of adult neurogenesis is thus advancing our knowledge of the molecular cues in use for the activation of NSCs and fate of their progeny. Because the regenerative potential of somatic stem cells generally weakens with increasing age, it is important to assess the extent to which zebrafish NSC potential decreases or remains unaltered with age. We found that neurogenesis in the ventricular zone, in the olfactory bulb, and in a newly identified parenchymal zone of the telencephalon indeed declines as the fish ages and that oligodendrogenesis also declines. In the ventricular zone, the radial glial cell population remains largely unaltered morphologically but enters less frequently into the cell cycle and hence produces fewer neuroblasts. The neuroblasts themselves do not change their behavior with age and produce the same number of postmitotic neurons. Thus, decreased neurogenesis in the physiologically aging zebrafish brain is correlated with an increasing quiescence of radial glia. After injuries, radial glia in aged brains are reactivated, and the percentage of cell cycle entry is increased in the radial glia population. However, this reaction is far less pronounced than in younger animals, pointing to irreversible changes in aging zebrafish radial glia. Copyright © 2013 Wiley Periodicals, Inc.

Collective cell migration without proliferation: density determines cell velocity and wave velocity

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Tlili, Sham; Gauquelin, Estelle; Li, Brigitte; Cardoso, Olivier; Ladoux, Benoît; Delanoë-Ayari, Hélène; Graner, François

2018-05-01

Collective cell migration contributes to embryogenesis, wound healing and tumour metastasis. Cell monolayer migration experiments help in understanding what determines the movement of cells far from the leading edge. Inhibiting cell proliferation limits cell density increase and prevents jamming; we observe long-duration migration and quantify space-time characteristics of the velocity profile over large length scales and time scales. Velocity waves propagate backwards and their frequency depends only on cell density at the moving front. Both cell average velocity and wave velocity increase linearly with the cell effective radius regardless of the distance to the front. Inhibiting lamellipodia decreases cell velocity while waves either disappear or have a lower frequency. Our model combines conservation laws, monolayer mechanical properties and a phenomenological coupling between strain and polarity: advancing cells pull on their followers, which then become polarized. With reasonable values of parameters, this model agrees with several of our experimental observations. Together, our experiments and model disantangle the respective contributions of active velocity and of proliferation in monolayer migration, explain how cells maintain their polarity far from the moving front, and highlight the importance of strain-polarity coupling and density in long-range information propagation.

Adult neurogenesis is reduced in the dorsal hippocampus of rats displaying learned helplessness behavior.

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Ho, Y C; Wang, S

2010-11-24

Clinical and preclinical studies suggest that the hippocampus has a role in the pathophysiology of major depression. In the learned helplessness (LH) animal model of depression after inescapable shocks (ISs) animals that display LH behavior have reduced cell proliferation in the hippocampus; this effect can be reversed by antidepressant treatment. Using this model, we compared rats that displayed LH behavior and rats that did not show LH behavior (NoLH) after ISs to determine whether reduced hippocampal cell proliferation is associated with the manifestation of LH behavior or is a general response to stress. Specifically, we examined cell proliferation, neurogenesis, and synaptic function in dorsal and ventral hippocampus of LH and NoLH animals and control rats that were not shocked. The LH rats had showed reduced cell proliferation, neurogenesis, and synaptic transmission in the dorsal hippocampus, whereas no changes were seen in the ventral hippocampus. These changes were not observed in the NoLH animals. In a group of NoLH rats that received the same amount of electrical shock as the LH rats to control for the unequal shocks received in these two groups, we observed changes in Ki-67(+) cells associated with acute stress. We conclude that reduced hippocampal cell proliferation and neurogenesis are associated with the manifestation of LH behavior and that the dorsal hippocampus is the most affected area. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Plasticity of Cell Migration In Vivo and In Silico

NARCIS (Netherlands)

Boekhorst, V. Te; Preziosi, L.; Friedl, P.

2016-01-01

Cell migration results from stepwise mechanical and chemical interactions between cells and their extracellular environment. Mechanistic principles that determine single-cell and collective migration modes and their interconversions depend upon the polarization, adhesion, deformability,

Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting

DEFF Research Database (Denmark)

Munthe, Sune; Sørensen, Mia D; Thomassen, Mads

2016-01-01

Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem......-like phenotype is currently lacking. In the present study, the aim was to characterize the phenotype of migrating tumor cells using a novel migration assay based on serum-free stem cell medium and patient-derived spheroid cultures. The results showed pronounced migration of five different GBM spheroid cultures......-related genes and the HOX-gene list in migrating cells compared to spheroids. Determination of GBM molecular subtypes revealed that subtypes of spheroids and migrating cells were identical. In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since...

Robotic Patterning a Superhydrophobic Surface for Collective Cell Migration Screening.

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Pang, Yonggang; Yang, Jing; Hui, Zhixin; Grottkau, Brian E

2018-04-01

Collective cell migration, in which cells migrate as a group, is fundamental in many biological and pathological processes. There is increasing interest in studying the collective cell migration in high throughput. Cell scratching, insertion blocker, and gel-dissolving techniques are some methodologies used previously. However, these methods have the drawbacks of cell damage, substrate surface alteration, limitation in medium exchange, and solvent interference. The superhydrophobic surface, on which the water contact angle is greater than 150 degrees, has been recently utilized to generate patterned arrays. Independent cell culture areas can be generated on a substrate that functions the same as a conventional multiple well plate. However, so far there has been no report on superhydrophobic patterning for the study of cell migration. In this study, we report on the successful development of a robotically patterned superhydrophobic array for studying collective cell migration in high throughput. The array was developed on a rectangular single-well cell culture plate consisting of hydrophilic flat microwells separated by the superhydrophobic surface. The manufacturing process is robotic and includes patterning discrete protective masks to the substrate using 3D printing, robotic spray coating of silica nanoparticles, robotic mask removal, robotic mini silicone blocker patterning, automatic cell seeding, and liquid handling. Compared with a standard 96-well plate, our system increases the throughput by 2.25-fold and generates a cell-free area in each well non-destructively. Our system also demonstrates higher efficiency than conventional way of liquid handling using microwell plates, and shorter processing time than manual operating in migration assays. The superhydrophobic surface had no negative impact on cell viability. Using our system, we studied the collective migration of human umbilical vein endothelial cells and cancer cells using assays of endpoint

Integrins in cell migration – the actin connection

OpenAIRE

Vicente-Manzanares, Miguel; Choi, Colin Kiwon; Horwitz, Alan Rick

2008-01-01

The connection between integrins and actin is driving the field of cell migration in new directions. Integrins and actin are coupled through a physical linkage, which provides traction for migration. Recent studies show the importance of this linkage in regulating adhesion organization and development. Actin polymerization orchestrates adhesion assembly near the leading edge of a migrating cell, and the dynamic cross-linking of actin filaments promotes adhesion maturat...

Cell Migration in 1D and 2D Nanofiber Microenvironments.

Science.gov (United States)

Estabridis, Horacio M; Jana, Aniket; Nain, Amrinder; Odde, David J

2018-03-01

Understanding how cells migrate in fibrous environments is important in wound healing, immune function, and cancer progression. A key question is how fiber orientation and network geometry influence cell movement. Here we describe a quantitative, modeling-based approach toward identifying the mechanisms by which cells migrate in fibrous geometries having well controlled orientation. Specifically, U251 glioblastoma cells were seeded onto non-electrospinning Spinneret based tunable engineering parameters fiber substrates that consist of networks of suspended 400 nm diameter nanofibers. Cells were classified based on the local fiber geometry and cell migration dynamics observed by light microscopy. Cells were found in three distinct geometries: adhering two a single fiber, adhering to two parallel fibers, and adhering to a network of orthogonal fibers. Cells adhering to a single fiber or two parallel fibers can only move in one dimension along the fiber axis, whereas cells on a network of orthogonal fibers can move in two dimensions. We found that cells move faster and more persistently in 1D geometries than in 2D, with cell migration being faster on parallel fibers than on single fibers. To explain these behaviors mechanistically, we simulated cell migration in the three different geometries using a motor-clutch based model for cell traction forces. Using nearly identical parameter sets for each of the three cases, we found that the simulated cells naturally replicated the reduced migration in 2D relative to 1D geometries. In addition, the modestly faster 1D migration on parallel fibers relative to single fibers was captured using a correspondingly modest increase in the number of clutches to reflect increased surface area of adhesion on parallel fibers. Overall, the integrated modeling and experimental analysis shows that cell migration in response to varying fibrous geometries can be explained by a simple mechanical readout of geometry via a motor-clutch mechanism.

An automated cell-counting algorithm for fluorescently-stained cells in migration assays

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Novielli Nicole M

2011-10-01

Full Text Available Abstract A cell-counting algorithm, developed in Matlab®, was created to efficiently count migrated fluorescently-stained cells on membranes from migration assays. At each concentration of cells used (10,000, and 100,000 cells, images were acquired at 2.5 ×, 5 ×, and 10 × objective magnifications. Automated cell counts strongly correlated to manual counts (r2 = 0.99, P

Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model.

Science.gov (United States)

Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E; Shi, Yanhong

2014-06-24

The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders

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Fabio Cavaliere

2016-01-01

Full Text Available Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson’s disease, and cerebral ischemia.

Enriched Environment Increases PCNA and PARP1 Levels in Octopus vulgaris Central Nervous System: First Evidence of Adult Neurogenesis in Lophotrochozoa.

Science.gov (United States)

Bertapelle, Carla; Polese, Gianluca; Di Cosmo, Anna

2017-06-01

Organisms showing a complex and centralized nervous system, such as teleosts, amphibians, reptiles, birds and mammals, and among invertebrates, crustaceans and insects, can adjust their behavior according to the environmental challenges. Proliferation, differentiation, migration, and axonal and dendritic development of newborn neurons take place in brain areas where structural plasticity, involved in learning, memory, and sensory stimuli integration, occurs. Octopus vulgaris has a complex and centralized nervous system, located between the eyes, with a hierarchical organization. It is considered the most "intelligent" invertebrate for its advanced cognitive capabilities, as learning and memory, and its sophisticated behaviors. The experimental data obtained by immunohistochemistry and western blot assay using proliferating cell nuclear antigen and poli (ADP-ribose) polymerase 1 as marker of cell proliferation and synaptogenesis, respectively, reviled cell proliferation in areas of brain involved in learning, memory, and sensory stimuli integration. Furthermore, we showed how enriched environmental conditions affect adult neurogenesis. © 2017 Wiley Periodicals, Inc.

Inhibition of Rho-associated kinases disturbs the collective cell migration of stratified TE-10 cells

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Taro Mikami

2015-01-01

Full Text Available BACKGROUND: The collective cell migration of stratified epithelial cells is considered to be an important phenomenon in wound healing, development, and cancer invasion; however, little is known about the mechanisms involved. Furthermore, whereas Rho family proteins, including RhoA, play important roles in cell migration, the exact role of Rho-associated coiled coil-containing protein kinases (ROCKs in cell migration is controversial and might be cell-type dependent. Here, we report the development of a novel modified scratch assay that was used to observe the collective cell migration of stratified TE-10 cells derived from a human esophageal cancer specimen. RESULTS: Desmosomes were found between the TE-10 cells and microvilli of the surface of the cell sheet. The leading edge of cells in the cell sheet formed a simple layer and moved forward regularly; these rows were followed by the stratified epithelium. ROCK inhibitors and ROCK small interfering RNAs (siRNAs disturbed not only the collective migration of the leading edge of this cell sheet, but also the stratified layer in the rear. In contrast, RhoA siRNA treatment resulted in more rapid migration of the leading rows and disturbed movement of the stratified portion. CONCLUSIONS: The data presented in this study suggest that ROCKs play an important role in mediating the collective migration of TE-10 cell sheets. In addition, differences between the effects of siRNAs targeting either RhoA or ROCKs suggested that distinct mechanisms regulate the collective cell migration in the simple epithelium of the wound edge versus the stratified layer of the epithelium.

Delayed behavioral dysfunctions following exposure to ionising radiation: role of neurogenesis

International Nuclear Information System (INIS)

Haridas, Seenu; Kumar, Mayank; Manda, Kailash

2014-01-01

Being a terminally differentiated organ, the brain has been considered to be a radioresistant one. Traditionally, delayed radiation-induced CNS damage was hypothesized as chiefly attributable to impaired vascular endothelial system and neuroinflammatory glial cell populations. In the recent decades, preclinical studies have focused on the hippocampal dentate gyrus, one of two discrete sites of the brain where adult neurogenesis takes place. Neurogenesis, in such area of the brain takes place throughout the adulthood and makes the brain highly vulnerable to the radiation. Recent investigations, including our own reports indicated that radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Since the hippocampus is involved in learning and memory, behavioral adaptation and HPA axis regulation, damage by radiation leads to severe behavioral and cognitive dysfunctions. The present study aimed at evaluating the delayed effects of gamma-irradiation on the cognitive and affective functions, which were further corroborated to changes in neurogenesis. C57BL/6J mice were exposed to whole body irradiation as well as cranial irradiation by gamma-rays at different sub-lethal doses. The behavioral tests, consisting spontaneous motor activity, open field test, novel object recognition test, forced swim test and Morris water maze were performed at 1 month and 5 months post-exposure. Neurogenic potential was evaluated using flow-cytometry (FC) and immuno-histo-chemistry (IHC). The results indicated the significant changes in the affective and cognitive functions at delayed time points of radiation exposure. Profound alteration in the anxiety and depressive phenotype was observed following irradiation. Additionally, both long term and short term memory functions were disrupted, which were attributable to changes in the neurogenic potential as reported in the terms of BrdU positive cells using FC and IHC. Present investigation clearly

Neurotransmitter regulation of adult neurogenesis: putative therapeutic targets.

Science.gov (United States)

Vaidya, V A; Vadodaria, K C; Jha, S

2007-10-01

The evidence that new neuron addition takes place in the mammalian brain throughout adult life has dramatically altered our perspective of the potential for plasticity in the adult CNS. Although several recent reports suggest a latent neurogenic capacity in multiple brain regions, the two major neurogenic niches that retain the ability to generate substantial numbers of new neurons in adult life are the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) in the hippocampal formation. The discovery of adult neurogenesis has also unveiled a novel therapeutic target for the repair of damaged neuronal circuits. In this regard, understanding the endogenous mechanisms that regulate adult neurogenesis holds promise both for a deeper understanding of this form of structural plasticity, as well as the identification of pathways that can serve as therapeutic targets to manipulate adult neurogenesis. The purpose of the present review is to discuss the regulation of adult neurogenesis by neurotransmitters and to highlight the relevance of these endogenous regulators as targets to modulate adult neurogenesis in a clinical context.

Collective cell migration in morphogenesis, regeneration and cancer.

NARCIS (Netherlands)

Friedl, P.H.A.; Gilmour, D.

2009-01-01

The collective migration of cells as a cohesive group is a hallmark of the tissue remodelling events that underlie embryonic morphogenesis, wound repair and cancer invasion. In such migration, cells move as sheets, strands, clusters or ducts rather than individually, and use similar actin- and

Adult neurogenesis modifies excitability of the dentate gyrus

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Taruna eIkrar

2013-12-01

Full Text Available Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the granule cell layer (GCL is conducive for pattern separation. A sparse coding scheme is thought to facilitate the distribution of similar entorhinal inputs across the GCL to decorrelate overlapping representations and minimize interference. Here we used fast voltage-sensitive dye (VSD imaging combined with laser photostimulation and electrical stimulation to examine how selectively increasing adult DG neurogenesis influences local circuit activity and excitability. We show that DG of mice with more adult-born neurons exhibits decreased strength of neuronal activation and more restricted excitation spread in GCL while maintaining effective output to CA3c. Conversely, blockade of adult hippocampal neurogenesis changed excitability of the DG in the opposite direction. Analysis of GABAergic inhibition onto mature dentate granule neurons in the DG of mice with more adult-born neurons shows a modest readjustment of perisomatic inhibitory synaptic gain without changes in overall inhibitory tone, presynaptic properties or GABAergic innervation pattern. Retroviral labeling of connectivity in mice with more adult-born neurons showed increased number of excitatory synaptic contacts of adult-born neurons onto hilar interneurons. Together, these studies demonstrate that adult hippocampal neurogenesis modifies excitability of mature dentate granule neurons and that this non-cell autonomous effect may be mediated by local circuit mechanisms such as excitatory drive onto hilar interneurons. Modulation of DG excitability by adult-born dentate granule neurons may enhance sparse coding in the GCL to influence pattern

Balancing Cell Migration with Matrix Degradation Enhances Gene Delivery to Cells Cultured Three-Dimensionally Within Hydrogels

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Shepard, Jaclyn A.; Huang, Alyssa; Shikanova, Ariella; Shea, Lonnie D.

2010-01-01

In regenerative medicine, hydrogels are employed to fill defects and support the infiltration of cells that can ultimately regenerate tissue. Gene delivery within hydrogels targeting infiltrating cells has the potential to promote tissue formation, but the delivery efficiency of nonviral vectors within hydrogels is low hindering their applicability in tissue regeneration. To improve their functionality, we have conducted a mechanistic study to investigate the contribution of cell migration and matrix degradation on gene delivery. In this report, lipoplexes were entrapped within hydrogels based on poly(ethylene glycol) (PEG) crosslinked with peptides containing matrix metalloproteinase degradable sequences. The mesh size of these hydrogels is substantially less than the size of the entrapped lipoplexes, which can function to retain vectors. Cell migration and transfection were simultaneously measured within hydrogels with varying density of cell adhesion sites (Arg-Gly-Asp peptides) and solids content. Increasing RGD density increased expression levels up to 100-fold, while greater solids content sustained expression levels for 16 days. Increasing RGD density and decreasing solids content increased cell migration, which indicates expression levels increase with increased cell migration. Initially exposing cells to vector resulted in transient expression that declined after 2 days, verifying the requirement of migration to sustain expression. Transfected cells were predominantly located within the population of migrating cells for hydrogels that supported cell migration. Although the small mesh size retained at least 70% of the lipoplexes in the absence of cells after 32 days, the presence of cells decreased retention to 10% after 16 days. These results indicate that vectors retained within hydrogels contact migrating cells, and that persistent cell migration can maintain elevated expression levels. Thus matrix degradation and cell migration are fundamental design

Perlecan controls neurogenesis in the developing telencephalon

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Fairén Alfonso

2007-04-01

Full Text Available Abstract Background Perlecan is a proteoglycan expressed in the basal lamina of the neuroepithelium during development. Perlecan absence does not impair basal lamina assembly, although in the 55% of the mutants early disruptions of this lamina conducts to exencephaly, impairing brain development. The rest of perlecan-null brains complete its prenatal development, maintain basal lamina continuity interrupted by some isolated ectopias, and are microcephalic. Microcephaly consists of thinner cerebral walls and underdeveloped ganglionic eminences. We have studied the mechanisms that generate brain atrophy in telencephalic areas where basal lamina is intact. Results Brain atrophy in the absence of perlecan started in the ventral forebrain and extended to lateral and dorsal parts of the cortex in the following stages. First, the subpallial forebrain developed poorly in early perlecan-null embryos, because of a reduced cell proliferation: the number of cells in mitosis decreased since the early stages of development. This reduction resulted in a decreased tangential migration of interneurons to the cerebral cortex. Concomitant with the early hypoplasia observed in the medial ganglionic eminences, Sonic Hedgehog signal decreased in the perlecan-null floor plate basal lamina at E12.5. Second, neurogenesis in the pallial neuroepithelium was affected in perlecan deficient embryos. We found reductions of nearly 50% in the number of cells exiting the cell cycle at E12–E13. The labeling index, which was normal at this age, significantly decreased with advancing corticogenesis. Moreover, nestin+ or PCNA+ progenitors increased since E14.5, reaching up to about 150% of the proportion of PCNA+ cells in the wild-type at E17.5. Thus, labeling index reduction together with increased progenitor population, suggests that atrophy is the result of altered cell cycle progression in the cortical progenitors. Accordingly, less neurons populated the cortical plate and

Computational modelling of multi-cell migration in a multi-signalling substrate

International Nuclear Information System (INIS)

Mousavi, Seyed Jamaleddin; Doblaré, Manuel; Doweidar, Mohamed Hamdy

2014-01-01

Cell migration is a vital process in many biological phenomena ranging from wound healing to tissue regeneration. Over the past few years, it has been proven that in addition to cell–cell and cell-substrate mechanical interactions (mechanotaxis), cells can be driven by thermal, chemical and/or electrical stimuli. A numerical model was recently presented by the authors to analyse single cell migration in a multi-signalling substrate. That work is here extended to include multi-cell migration due to cell–cell interaction in a multi-signalling substrate under different conditions. This model is based on balancing the forces that act on the cell population in the presence of different guiding cues. Several numerical experiments are presented to illustrate the effect of different stimuli on the trajectory and final location of the cell population within a 3D heterogeneous multi-signalling substrate. Our findings indicate that although multi-cell migration is relatively similar to single cell migration in some aspects, the associated behaviour is very different. For instance, cell–cell interaction may delay single cell migration towards effective cues while increasing the magnitude of the average net cell traction force as well as the local velocity. Besides, the random movement of a cell within a cell population is slightly greater than that of single cell migration. Moreover, higher electrical field strength causes the cell slug to flatten near the cathode. On the other hand, as with single cell migration, the existence of electrotaxis dominates mechanotaxis, moving the cells to the cathode or anode pole located at the free surface. The numerical results here obtained are qualitatively consistent with related experimental works. (paper)

The male sex pheromone darcin stimulates hippocampal neurogenesis and cell proliferation in the subventricular zone in female mice

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Emma eHoffman

2015-04-01

Full Text Available The integration of newly generated neurons persists throughout life in the mammalian olfactory bulb and hippocampus, regions involved in olfactory and spatial learning. Social cues can be potent stimuli for increasing adult neurogenesis; for example, odors from dominant but not subordinate male mice increase neurogenesis in both brain regions of adult females. However, little is known about the role of neurogenesis in social recognition or the assessment of potential mates. Dominant male mice scent-mark territories using urine that contains a number of pheromones including darcin (MUP20, a male-specific major urinary protein that stimulates rapid learned attraction to the spatial location and individual odor signature of the scent owner. Here we investigate whether exposure to darcin stimulates neurogenesis in the female brain. Hippocampal neurons and cellular proliferation in the lateral ventricles that supply neurons to the olfactory bulbs increased in females exposed for seven days to male urine containing at least 0.5µg/µl darcin. Darcin was effective whether presented alone or in the context of male urine, but other information in male urine appeared to modulate the proliferative response. When exposed to urine from wild male mice, hippocampal proliferation increased only if urine was from the same individual over seven days, suggesting that consistency of individual scent signatures is important. While seven days exposure to male scent initiated the first stages of increased neurogenesis, this caused no immediate increase in female attraction to the scent or in the strength or robustness of spatial learning in short-term conditioned place preference tests. The reliable and consistent stimulation of neurogenesis by a pheromone important in rapid social learning suggests that this may provide an excellent model to explore the relationship between the integration of new neurons and plasticity in spatial and olfactory learning in a socially

HIPPOCAMPAL ADULT NEUROGENESIS: ITS REGULATION AND POTENTIAL ROLE IN SPATIAL LEARNING AND MEMORY

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Lieberwirth, Claudia; Pan, Yongliang; Liu, Yan; Zhang, Zhibin; Wang, Zuoxin

2016-01-01

Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk). PMID:27174001

Using Single-Protein Tracking to Study Cell Migration.

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Orré, Thomas; Mehidi, Amine; Massou, Sophie; Rossier, Olivier; Giannone, Grégory

2018-01-01

To get a complete understanding of cell migration, it is critical to study its orchestration at the molecular level. Since the recent developments in single-molecule imaging, it is now possible to study molecular phenomena at the single-molecule level inside living cells. In this chapter, we describe how such approaches have been and can be used to decipher molecular mechanisms involved in cell migration.

Automated Tracking of Cell Migration with Rapid Data Analysis.

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DuChez, Brian J

2017-09-01

Cell migration is essential for many biological processes including development, wound healing, and metastasis. However, studying cell migration often requires the time-consuming and labor-intensive task of manually tracking cells. To accelerate the task of obtaining coordinate positions of migrating cells, we have developed a graphical user interface (GUI) capable of automating the tracking of fluorescently labeled nuclei. This GUI provides an intuitive user interface that makes automated tracking accessible to researchers with no image-processing experience or familiarity with particle-tracking approaches. Using this GUI, users can interactively determine a minimum of four parameters to identify fluorescently labeled cells and automate acquisition of cell trajectories. Additional features allow for batch processing of numerous time-lapse images, curation of unwanted tracks, and subsequent statistical analysis of tracked cells. Statistical outputs allow users to evaluate migratory phenotypes, including cell speed, distance, displacement, and persistence, as well as measures of directional movement, such as forward migration index (FMI) and angular displacement. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Nucleus and nucleus-cytoskeleton connections in 3D cell migration

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Liu, Lingling, E-mail: liulingling2012@163.com; Luo, Qing, E-mail: qing.luo@cqu.edu.cn; Sun, Jinghui, E-mail: sunjhemail@163.com; Song, Guanbin, E-mail: song@cqu.edu.cn

2016-10-15

Cell migration plays an important role in many physiological and pathological settings, ranging from embryonic development to cancer metastasis. Currently, accumulating data suggest that cells migrating in three-dimensional (3D) environments show well-defined differences compared to their well-established two-dimensional (2D) counterparts. During 3D migration, the cell body and nucleus must deform to allow cellular passage through the available spaces, and the deformability of the relatively rigid nucleus may constitute a limiting step. Here, we highlight the key evidence regarding the role of the nuclear mechanics in 3D migration, including the molecular components that govern the stiffness of the nucleus and review how the nuclear dynamics are connected to and controlled by cytoskeleton-based migration machinery. Intriguingly, nuclear movement must be coordinated with the cytoskeletal dynamics at the leading and trailing edges, which in turn impact the cytoplasmic dynamics that affect the migration efficiency. Thus, we suggest that alterations in the nuclear structure may facilitate cellular reorganizations that are necessary for efficient migration. - Graphical abstract: Schematic representations of a cell migrating on a 2D substrate and a cell migrating in a 3D extracellular matrix environment. (A) Nucleus-cytoskeleton connections are essential to 3D migration. Mechanical signals are transduced by integrins at the cell surface and channeled to cytoskeletal proteins, which generates prestress. The nucleus-cytoskeleton connections can either act as a stable skeleton to anchor the nuclei or provide active force to move the nuclei. The LINC complex is responsible for the nucleo-cytoskeletal coupling. Nesprins connect the cytoskeletal proteins to the inner nuclear membrane proteins SUN1 and SUN2. The SUN proteins connect to the lamins that form the lamina, which attaches to the chromatin. This physical connectivity transmits the mechanical signals from receptors at

Nucleus and nucleus-cytoskeleton connections in 3D cell migration

International Nuclear Information System (INIS)

Liu, Lingling; Luo, Qing; Sun, Jinghui; Song, Guanbin

2016-01-01

Cell migration plays an important role in many physiological and pathological settings, ranging from embryonic development to cancer metastasis. Currently, accumulating data suggest that cells migrating in three-dimensional (3D) environments show well-defined differences compared to their well-established two-dimensional (2D) counterparts. During 3D migration, the cell body and nucleus must deform to allow cellular passage through the available spaces, and the deformability of the relatively rigid nucleus may constitute a limiting step. Here, we highlight the key evidence regarding the role of the nuclear mechanics in 3D migration, including the molecular components that govern the stiffness of the nucleus and review how the nuclear dynamics are connected to and controlled by cytoskeleton-based migration machinery. Intriguingly, nuclear movement must be coordinated with the cytoskeletal dynamics at the leading and trailing edges, which in turn impact the cytoplasmic dynamics that affect the migration efficiency. Thus, we suggest that alterations in the nuclear structure may facilitate cellular reorganizations that are necessary for efficient migration. - Graphical abstract: Schematic representations of a cell migrating on a 2D substrate and a cell migrating in a 3D extracellular matrix environment. (A) Nucleus-cytoskeleton connections are essential to 3D migration. Mechanical signals are transduced by integrins at the cell surface and channeled to cytoskeletal proteins, which generates prestress. The nucleus-cytoskeleton connections can either act as a stable skeleton to anchor the nuclei or provide active force to move the nuclei. The LINC complex is responsible for the nucleo-cytoskeletal coupling. Nesprins connect the cytoskeletal proteins to the inner nuclear membrane proteins SUN1 and SUN2. The SUN proteins connect to the lamins that form the lamina, which attaches to the chromatin. This physical connectivity transmits the mechanical signals from receptors at

Loss of myoferlin redirects breast cancer cell motility towards collective migration.

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Leonithas I Volakis

Full Text Available Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET and reduced invasion through extracellular matrix (ECM. However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231(MYOF-KD leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA-231(LTVC and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA-231(MYOF-KD cells migrated directionally and collectively, while MDA-231(LTVC cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231(MYOF-KD cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA-231(MYOF-KD cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA-231(MYOF-KD tumors were highly circularized and did not invade locally into the adventia in contrast to MDA-231(LTVC-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate

Absence of Tangentially Migrating Glutamatergic Neurons in the Developing Avian Brain

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Fernando García-Moreno

2018-01-01

Full Text Available Summary: Several neuronal populations orchestrate neocortical development during mammalian embryogenesis. These include the glutamatergic subplate-, Cajal-Retzius-, and ventral pallium-derived populations, which coordinate cortical wiring, migration, and proliferation, respectively. These transient populations are primarily derived from other non-cortical pallial sources that migrate to the dorsal pallium. Are these migrations to the dorsal pallium conserved in amniotes or are they specific to mammals? Using in ovo electroporation, we traced the entire lineage of defined chick telencephalic progenitors. We found that several pallial sources that produce tangential migratory neurons in mammals only produced radially migrating neurons in the avian brain. Moreover, ectopic expression of VP-specific mammalian Dbx1 in avian brains altered neurogenesis but did not convert the migration into a mammal-like tangential movement. Together, these data indicate that tangential cellular contributions of glutamatergic neurons originate from outside the dorsal pallium and that pallial Dbx1 expression may underlie the generation of the mammalian neocortex during evolution. : Neocortical formation crucially depends on the early tangential arrival of several transient glutamatergic neuronal populations. García-Moreno et al. find that these neuronal migrations are absent in the developing brain of chicks. The mammalian uniqueness of these developing migrations suggests a crucial role of these cells in the evolutionary origin of the neocortex. Keywords: neocortex, chick, pallium, ventral pallium, evo-devo, evolution, Dbx1, telencephalon

SOX15 regulates proliferation and migration of endometrial cancer cells.

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Rui, Xiaohui; Xu, Yun; Jiang, Xiping; Guo, Caixia; Jiang, Jingting

2017-10-31

The study aimed to investigate the effects of Sry-like high mobility group box 15 ( SOX15 ) on proliferation and migration of endometrial cancer (EC) cells. Immunohistochemistry (IHC) was applied to determine the expression of SOX15 in EC tissues and adjacent tissues. We used cell transfection method to construct the HEC-1-A and Ishikawa cell lines with stable overexpression and low expression SOX15 Reverse-transcription quantitative real-time PCR (RT-qPCR) and Western blot were performed to examine expression of SOX15 mRNA and SOX15 protein, respectively. By conducting a series of cell proliferation assay and migration assay, we analyzed the influence of SOX15 overexpression or low expression on EC cell proliferation and migration. The expression of SOX15 mRNA and protein in EC tissues was significantly lower than that in adjacent tissues. After lentivirus-transfecting SOX15 , the expression level of SOX15 mRNA and protein was significantly increased in cells of SOX15 group, and decreased in sh- SOX15 group. Overexpression of SOX15 could suppress cell proliferation, while down-regulation of SOX15 increased cell proliferation. Flow cytometry results indicated that overexpression of SOX15 induced the ratio of cell-cycle arrest in G 1 stage. In addition, Transwell migration assay results showed that SOX15 overexpression significantly inhibited cell migration, and also down-regulation of SOX15 promoted the migration. As a whole, SOX15 could regulate the proliferation and migration of EC cells and up- regulation of SOX15 could be valuable for EC treatment. © 2017 The Author(s).

The thioredoxin system in breast cancer cell invasion and migration

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Maneet Bhatia

2016-08-01

Full Text Available Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1 in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1 expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.

Magnetic resonance beacon to detect intracellular microRNA during neurogenesis.

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Lee, Jonghwan; Jin, Yeon A; Ko, Hae Young; Lee, Yong Seung; Heo, Hyejung; Cho, Sujeong; Kim, Soonhag

2015-02-01

Magnetic resonance imaging (MRI) offers great spatial resolution for viewing deep tissues and anatomy. We developed a self-assembling signal-on magnetic fluorescence nanoparticle to visualize intracellular microRNAs (miRNAs or miRs) during neurogenesis using MRI. The self-assembling nanoparticle (miR124a MR beacon) was aggregated by the incubation of three different oligonucleotides: a 3' adaptor, a 5' adaptor, and a linker containing miR124a-binding sequences. The T2-weighted magnetic resonance (MR) signal of the self-assembled nanoparticle was quenched when miR124a was absent from test tubes or was minimally expressed in cells and tissues. When miR124a was present in test tubes or highly expressed in vitro and in vivo during P19 cell neurogenesis, it hybridized with the miR124a MR beacon, causing the linker to detach, resulting in increased signal-on MRI intensity. This MR beacon can be used as a new imaging probe to monitor the miRNA-mediated regulation of cellular processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Protein kinase Cepsilon is important for migration of neuroblastoma cells

International Nuclear Information System (INIS)

Stensman, Helena; Larsson, Christer

2008-01-01

Migration is important for the metastatic capacity and thus for the malignancy of cancer cells. There is limited knowledge on regulatory factors that promote the migration of neuroblastoma cells. This study investigates the hypothesis that protein kinase C (PKC) isoforms regulate neuroblastoma cell motility. PKC isoforms were downregulated with siRNA or modulated with activators and inhibitors. Migration was analyzed with scratch and transwell assays. Protein phosphorylation and expression levels were measured with Western blot. Stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced migration of SK-N-BE(2)C neuroblastoma cells. Treatment with the general protein kinase C (PKC) inhibitor GF109203X and the inhibitor of classical isoforms Gö6976 inhibited migration while an inhibitor of PKCβ isoforms did not have an effect. Downregulation of PKCε, but not of PKCα or PKCδ, with siRNA led to a suppression of both basal and TPA-stimulated migration. Experiments using PD98059 and LY294002, inhibitors of the Erk and phosphatidylinositol 3-kinase (PI3K) pathways, respectively, showed that PI3K is not necessary for TPA-induced migration. The Erk pathway might be involved in TPA-induced migration but not in migration driven by PKCε. TPA induced phosphorylation of the PKC substrate myristoylated alanine-rich C kinase substrate (MARCKS) which was suppressed by the PKC inhibitors. Treatment with siRNA oligonucleotides against different PKC isoforms before stimulation with TPA did not influence the phosphorylation of MARCKS. PKCε is important for migration of SK-N-BE(2)C neuroblastoma cells. Neither the Erk pathway nor MARCKS are critical downstream targets of PKCε but they may be involved in TPA-mediated migration

Estradiol-induced neurogenesis in the female accessory olfactory bulb is required for the learning of the male odor.

Science.gov (United States)

Brus, Maïna; Trouillet, Anne-Charlotte; Hellier, Vincent; Bakker, Julie

2016-08-01

Odors processed by the main and accessory olfactory bulbs (MOB, AOB) are important for sexual behavior. Interestingly, both structures continue to receive new neurons during adulthood. A role for olfactory neurogenesis in sexual behavior in female mice has recently been shown and gonadal hormones such as estradiol can modulate adult neurogenesis. Therefore, we wanted to determine the role of estradiol in learning the odors of sexual partners and in the adult neurogenesis of female aromatase knockout mice (ArKO), unable to produce estradiol. Female wild-type (WT) and ArKO mice were exposed to male odors during 7 days, and olfactory preferences, cell proliferation, cell survival and functional involvement of newborn neurons were analyzed, using BrdU injections, in combination with a marker of cell activation (Zif268) and neuronal fate (doublecortin, NeuN). Behavioral tasks indicated that both WT and ArKO females were able to discriminate between the odors of two different males, but ArKO mice failed to learn the familiar male odor. Proliferation of newborn cells was reduced in ArKO mice only in the dentate gyrus of the hippocampus. Olfactory exposure decreased cell survival in the AOB in WT females, suggesting a role for estradiol in a structure involved in sexual behavior. Finally, newborn neurons do not seem to be functionally involved in the AOB of ArKO mice compared with WT, when females were exposed to the odor of a familiar male, suggesting that estradiol-induced neurogenesis in the AOB is required for the learning of the male odor in female mice. Aromatase knockout mice (ArKO) presented deficits in olfactory preferences without affecting their olfactory discrimination abilities, and showed no functional involvement of newborn neurons in the accessory olfactory bulb (AOB) in response to the odor of a familiar male. These results suggest that estradiol-induced neurogenesis in the female AOB is required for the learning of the male odor. © 2016 International

Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms.

NARCIS (Netherlands)

Schmidt, S.; Friedl, P.H.A.

2010-01-01

Adhesion and migration are integrated cell functions that build, maintain and remodel the multicellular organism. In migrating cells, integrins are the main transmembrane receptors that provide dynamic interactions between extracellular ligands and actin cytoskeleton and signalling machineries. In

Novel perspectives of neural stem cell differentiation: from neurotransmitters to therapeutics.

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Trujillo, Cleber A; Schwindt, Telma T; Martins, Antonio H; Alves, Janaína M; Mello, Luiz Eugênio; Ulrich, Henning

2009-01-01

In the past years, many reports have described the existence of neural progenitor and stem cells in the adult central nervous system capable of generating new neurons, astrocytes, and oligodendrocytes. This discovery has overturned the central assumption in the neuroscience field, of no new neurons being originated in the brain after birth and provided the fundaments to understand the molecular basis of neural differentiation and to develop new therapies for neural tissue repair. Although the mechanisms underlying cell fate during neural development are not yet understood, the importance of intrinsic and extrinsic factors and of an appropriate microenvironment is well known. In this context, emerging evidence strongly suggests that glial cells play a key role in controlling multiple steps of neurogenesis. Those cells, of particular radial glia, are important for migration, cell specification, and integration of neurons into a functional neural network. This review aims to present an update in the neurogenesis area and highlight the modulation of neural stem cell differentiation by neurotransmitters, growth factors, and their receptors, with possible applications for cell therapy strategies of neurological disorders.

Bleb Expansion in Migrating Cells Depends on Supply of Membrane from Cell Surface Invaginations.

Science.gov (United States)

Goudarzi, Mohammad; Tarbashevich, Katsiaryna; Mildner, Karina; Begemann, Isabell; Garcia, Jamie; Paksa, Azadeh; Reichman-Fried, Michal; Mahabaleshwar, Harsha; Blaser, Heiko; Hartwig, Johannes; Zeuschner, Dagmar; Galic, Milos; Bagnat, Michel; Betz, Timo; Raz, Erez

2017-12-04

Cell migration is essential for morphogenesis, organ formation, and homeostasis, with relevance for clinical conditions. The migration of primordial germ cells (PGCs) is a useful model for studying this process in the context of the developing embryo. Zebrafish PGC migration depends on the formation of cellular protrusions in form of blebs, a type of protrusion found in various cell types. Here we report on the mechanisms allowing the inflation of the membrane during bleb formation. We show that the rapid expansion of the protrusion depends on membrane invaginations that are localized preferentially at the cell front. The formation of these invaginations requires the function of Cdc42, and their unfolding allows bleb inflation and dynamic cell-shape changes performed by migrating cells. Inhibiting the formation and release of the invaginations strongly interfered with bleb formation, cell motility, and the ability of the cells to reach their target. Copyright © 2017 Elsevier Inc. All rights reserved.

Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

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Moon, Minho; Jeong, Hyun Uk; Choi, Jin Gyu; Jeon, Seong Gak; Song, Eun Ji; Hong, Seon-Pyo; Oh, Myung Sook

2016-09-15

It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of cytokine treatment on the neurogenesis process in the brain of soman-poisoned mice

International Nuclear Information System (INIS)

Collombet, Jean-Marc; Four, Elise; Burckhart, Marie-France; Masqueliez, Catherine; Bernabe, Denis; Baubichon, Dominique; Herodin, Francis; Lallement, Guy

2005-01-01

We previously described that enhanced proliferation of neural progenitors occurred in the subgranular zone (SGZ) of the dentate gyrus and in the subventricular zone (SVZ) of the mouse brain following soman poisoning. Then, a discrete number of these cells seemed to migrate and engraft into the main damaged brain regions (hippocampus; septum and amygdala) and subsequently differentiate into neurons. In the present study, the effect of a cytokine treatment on the neurogenesis process was evaluated. For this purpose, subcutaneous injection of a cocktail of 40 μg/kg epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) was administered daily to soman-poisoned mice (110 μg/kg soman and 5.0 mg/kg methyl nitrate atropine), from post-soman days 1 to 8. To label replicating neural progenitors, 200 mg/kg bromodeoxyuridine (BrdU) was injected twice a day between post-soman days 6 and 8. Mice were sacrificed on post-soman day 9 or 34. On post-soman day 9, the cytokine treatment had no effect on the proliferation of neural progenitors in the SVZ and SGZ, as assessed by BrdU immunochemistry. However, this treatment seemed to promote the migration of neural precursor cells from the proliferative areas towards damaged brain regions. Indeed, in the CA1 hippocampal layer of soman-poisoned mice, on post-soman day 34, the cytokine treatment increased the number of healthy pyramidal neurons stained by hemalun-eosin dye. The cytokine treatment also augmented the number of BrdU-labeled cells in the CA1 hippocampal layer and amygdala. Interestingly, the administration of cytokines resulted in the differentiation of BrdU-positive cells into new neurons in the CA1 hippocampal layer, whereas astrocytic differentiation was preferentially observed in the amygdala

Oppositional effects of serotonin receptors 5-HT1a, 2 and 2c in the regulation of adult hippocampal neurogenesis

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Friederike Klempin

2010-07-01

Full Text Available Serotonin (5-HT appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lack acute effects on adult neurogenesis in many studies, which suggests a surprising long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self-renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT

Cadmium inhibits neurogenesis in zebrafish embryonic brain development

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Chow, Elly Suk Hen [Division of Biology, California Institute of Technology, 1200 California Boulevard, Pasadena, CA 91125 (United States); Hui, Michelle Nga Yu; Lin Chunchi [Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong (China); Cheng Shukhan [Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong (China)], E-mail: bhcheng@cityu.edu.hk

2008-05-01

Cadmium is a non-essential heavy metal found abundantly in the environment. Children of women exposed to cadmium during pregnancy display lower motor and perceptual abilities. High cadmium body burden in children is also related to impaired intelligence and lowered school achievement. However, little is known about the molecular and cellular basis of developmental neurotoxicity in the sensitive early life stages of animals. In this study, we explore neurological deficits caused by cadmium during early embryonic stages in zebrafish by examining regionalization of the neural tube, pattern formation and cell fate determination, commitment of proneural genes and induction of neurogenesis. We show that cadmium-treated embryos developed a smaller head with unclear boundaries between the brain subdivisions, particularly in the mid-hindbrain region. Embryos display normal anterior to posterior regionalization; however, the commitment of neural progenitor cells was affected by cadmium. We observe prominent reductions in the expression of several proneuronal genes including ngn1 in cell clusters, zash1a in the developing optic tectum, and zash1b in the telencephalon and tectum. Cadmium-treated embryos also have fewer differentiated neurons and glia in the facial sensory ganglia as indicated by decreased zn-12 expression. Also, a lower transcription level of neurogenic genes, ngn1 and neuroD, is observed in neurons. Our data suggest that cadmium-induced neurotoxicity can be caused by impaired neurogenesis, resulting in markedly reduced neuronal differentiation and axonogenesis.

Cadmium inhibits neurogenesis in zebrafish embryonic brain development

International Nuclear Information System (INIS)

Chow, Elly Suk Hen; Hui, Michelle Nga Yu; Lin Chunchi; Cheng Shukhan

2008-01-01

Cadmium is a non-essential heavy metal found abundantly in the environment. Children of women exposed to cadmium during pregnancy display lower motor and perceptual abilities. High cadmium body burden in children is also related to impaired intelligence and lowered school achievement. However, little is known about the molecular and cellular basis of developmental neurotoxicity in the sensitive early life stages of animals. In this study, we explore neurological deficits caused by cadmium during early embryonic stages in zebrafish by examining regionalization of the neural tube, pattern formation and cell fate determination, commitment of proneural genes and induction of neurogenesis. We show that cadmium-treated embryos developed a smaller head with unclear boundaries between the brain subdivisions, particularly in the mid-hindbrain region. Embryos display normal anterior to posterior regionalization; however, the commitment of neural progenitor cells was affected by cadmium. We observe prominent reductions in the expression of several proneuronal genes including ngn1 in cell clusters, zash1a in the developing optic tectum, and zash1b in the telencephalon and tectum. Cadmium-treated embryos also have fewer differentiated neurons and glia in the facial sensory ganglia as indicated by decreased zn-12 expression. Also, a lower transcription level of neurogenic genes, ngn1 and neuroD, is observed in neurons. Our data suggest that cadmium-induced neurotoxicity can be caused by impaired neurogenesis, resulting in markedly reduced neuronal differentiation and axonogenesis

Exposure to swainsonine impairs adult neurogenesis and spatial learning and memory.

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Wang, Jiutao; Song, Lingzhen; Zhang, Qi; Zhang, Wei; An, Lei; Zhang, Yamei; Tong, Dewen; Zhao, Baoyu; Chen, Shulin; Zhao, Shanting

2015-01-05

Swainsonine (SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. Ingestion induces severe neurological symptoms of livestock and wildlife, including ataxia, trembling, exaggerated fright reactions. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal a-mannosidase (AMA) and accumulation of intracellular oligosaccharide. However, the effects of SW on adult neurogenesis and cognition have remained unclear. Therefore, the present study was conducted to examine the effects of SW on adult neurogenesis and learning as well as memory performance in adult mice. SW (10μg/mL in drinking water) was administered orally to mice for 4 weeks. Our results showed that SW reduced proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of adult mice. In addition, exposure to SW led to down-regulation of doublecortin (DCX) and synaptophysin (SYP) in the hippocampus. However, caspase 3 and glial fibrillary acidic protein (GFAP) levels were significantly increased in SW-treated mice. Finally, SW-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that SW affects adult neurogenesis and cognitive function. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The Hippo pathway controls border cell migration through distinct mechanisms in outer border cells and polar cells of the Drosophila ovary.

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Lin, Tzu-Huai; Yeh, Tsung-Han; Wang, Tsu-Wei; Yu, Jenn-Yah

2014-11-01

The Hippo pathway is a key signaling cascade in controlling organ size. The core components of this pathway are two kinases, Hippo (Hpo) and Warts (Wts), and a transcriptional coactivator, Yorkie (Yki). Yes-associated protein (YAP, a Yki homolog in mammals) promotes epithelial-mesenchymal transition and cell migration in vitro. Here, we use border cells in the Drosophila ovary as a model to study Hippo pathway functions in cell migration in vivo. During oogenesis, polar cells secrete Unpaired (Upd), which activates JAK/STAT signaling of neighboring cells and specifies them into outer border cells. The outer border cells form a cluster with polar cells and undergo migration. We find that hpo and wts are required for migration of the border cell cluster. In outer border cells, overexpression of hpo disrupts polarization of the actin cytoskeleton and attenuates migration. In polar cells, knockdown of hpo and wts or overexpression of yki impairs border cell induction and disrupts migration. These manipulations in polar cells reduce JAK/STAT activity in outer border cells. Expression of upd-lacZ is increased and decreased in yki and hpo mutant polar cells, respectively. Furthermore, forced expression of upd in polar cells rescues defects of border cell induction and migration caused by wts knockdown. These results suggest that Yki negatively regulates border cell induction by inhibiting JAK/STAT signaling. Together, our data elucidate two distinct mechanisms of the Hippo pathway in controlling border cell migration: (1) in outer border cells, it regulates polarized distribution of the actin cytoskeleton; (2) in polar cells, it regulates upd expression to control border cell induction and migration. Copyright © 2014 by the Genetics Society of America.

Indirubin inhibits cell proliferation, migration, invasion and angiogenesis in tumor-derived endothelial cells

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Li Z

2018-05-01

Full Text Available Zhuohong Li, Chaofu Zhu, Baiping An, Yu Chen, Xiuyun He, Lin Qian, Lan Lan, Shijie Li Department of Oncology, The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China Purpose: Hepatocellular carcinoma is one of the most predominant malignancies with high fatality rate and its incidence is rising at an alarming rate because of its resistance to radio- and chemotherapy. Indirubin is the major active anti-tumor ingredient of a traditional Chinese herbal medicine. The present study aimed to analyze the effects of indirubin on cell proliferation, migration, invasion, and angiogenesis of tumor-derived endothelial cells (Td-EC. Methods: Td-EC were derived from human umbilical vein endothelial cells (HUVEC by treating HUVEC with the conditioned medium of human liver cancer cell line HepG2. Cell proliferation, migration, invasion, and angiogenesis were assessed by MTT, wound healing, in vitro cell invasion, and in vitro tube formation assay. Results: Td-EC were successfully obtained from HUVEC cultured with 50% culture supernatant from serum-starved HepG2 cells. Indirubin significantly inhibited Td-EC proliferation in a dose- and time-dependent manner. Indirubin also inhibited Td-EC migration, invasion, and angiogenesis. However, indirubin’s effects were weaker on HUVEC than Td-EC. Conclusion: Indirubin significantly inhibited Td-EC proliferation, migration, invasion, and angiogenesis. Keywords: indirubin, Td-EC, proliferation, migration, invasion, angiogenesis

Major unsolved points in adult neurogenesis: doors open on a translational future?

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Paolo ePeretto

2014-06-01

Full Text Available The ultimate goal of exploiting adult neurogenesis (AN as a source of cell replacement is far from being achieved. In spite of many data gathered during the last two decades on homeostatic and reactive neurogenesis, it is evident that such knowledge is not sufficient for granting translational outcomes. By asking the question whether AN research field has to be considered as a dead end in such a perspective, here we review some major unresolved issues: multifaceted evolutionary constraints emerged in mammals, stem/progenitor cell type/availability and tissue permissivity, the possible impact on other brain functions and/or interplay with other forms of plasticity, and relevance in humans. We suggest that full understanding of AN biological processes is an essential step to their possible exploitation for brain repair, and that further fundamental, multidisciplinary research is required before translational outcomes can be reached. Scientist's attitude and their communication skills are also important. To avoid overestimation of AN reparative potential, more distant goals of cell replacement should be kept clearly distinct from restorative approaches involving AN plasticity, both representing translational perspectives.

Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo.

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Barriga, Elias H; Franze, Kristian; Charras, Guillaume; Mayor, Roberto

2018-02-22

Collective cell migration is essential for morphogenesis, tissue remodelling and cancer invasion. In vivo, groups of cells move in an orchestrated way through tissues. This movement involves mechanical as well as molecular interactions between cells and their environment. While the role of molecular signals in collective cell migration is comparatively well understood, how tissue mechanics influence collective cell migration in vivo remains unknown. Here we investigated the importance of mechanical cues in the collective migration of the Xenopus laevis neural crest cells, an embryonic cell population whose migratory behaviour has been likened to cancer invasion. We found that, during morphogenesis, the head mesoderm underlying the cephalic neural crest stiffens. This stiffening initiates an epithelial-to-mesenchymal transition in neural crest cells and triggers their collective migration. To detect changes in their mechanical environment, neural crest cells use mechanosensation mediated by the integrin-vinculin-talin complex. By performing mechanical and molecular manipulations, we show that mesoderm stiffening is necessary and sufficient to trigger neural crest migration. Finally, we demonstrate that convergent extension of the mesoderm, which starts during gastrulation, leads to increased mesoderm stiffness by increasing the cell density underneath the neural crest. These results show that convergent extension of the mesoderm has a role as a mechanical coordinator of morphogenesis, and reveal a link between two apparently unconnected processes-gastrulation and neural crest migration-via changes in tissue mechanics. Overall, we demonstrate that changes in substrate stiffness can trigger collective cell migration by promoting epithelial-to-mesenchymal transition in vivo. More broadly, our results raise the idea that tissue mechanics combines with molecular effectors to coordinate morphogenesis.

Administration of Zinc plus Cyclo-(His-Pro Increases Hippocampal Neurogenesis in Rats during the Early Phase of Streptozotocin-Induced Diabetes

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Bo Young Choi

2017-01-01

Full Text Available The effects of zinc supplementation on hippocampal neurogenesis in diabetes mellitus have not been studied. Herein, we investigated the effects of zinc plus cyclo-(His-Pro (ZC on neurogenesis occurring in the subgranular zone of dentate gyrus after streptozotocin (STZ-induced diabetes. ZC (27 mg/kg was administered by gavage once daily for one or six weeks from the third day after the STZ injection, and histological evaluation was performed at 10 (early phase or 45 (late phase days after STZ injection. We found that the proliferation of progenitor cells in STZ-induced diabetic rats showed an increase in the early phase. Additionally, ZC treatment remarkably increased the number of neural progenitor cells (NPCs and immature neurons in the early phase of STZ-induced diabetic rats. Furthermore, ZC treatment showed increased survival rate of newly generated cells but no difference in the level of neurogenesis in the late phase of STZ-induced diabetic rats. The present study demonstrates that zinc supplementation by ZC increases both NPCs proliferation and neuroblast production at the early phase of diabetes. Thus, this study suggests that zinc supplemented with a histidine/proline complex may have beneficial effects on neurogenesis in patients experiencing the early phase of Type 1 diabetes.

Probing Leader Cells in Endothelial Collective Migration by Plasma Lithography Geometric Confinement.

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Yang, Yongliang; Jamilpour, Nima; Yao, Baoyin; Dean, Zachary S; Riahi, Reza; Wong, Pak Kin

2016-03-03

When blood vessels are injured, leader cells emerge in the endothelium to heal the wound and restore the vasculature integrity. The characteristics of leader cells during endothelial collective migration under diverse physiological conditions, however, are poorly understood. Here we investigate the regulation and function of endothelial leader cells by plasma lithography geometric confinement generated. Endothelial leader cells display an aggressive phenotype, connect to follower cells via peripheral actin cables and discontinuous adherens junctions, and lead migrating clusters near the leading edge. Time-lapse microscopy, immunostaining, and particle image velocimetry reveal that the density of leader cells and the speed of migrating clusters are tightly regulated in a wide range of geometric patterns. By challenging the cells with converging, diverging and competing patterns, we show that the density of leader cells correlates with the size and coherence of the migrating clusters. Collectively, our data provide evidence that leader cells control endothelial collective migration by regualting the migrating clusters.

Co-culture with Sertoli cells promotes proliferation and migration of umbilical cord mesenchymal stem cells

International Nuclear Information System (INIS)

Zhang, Fenxi; Hong, Yan; Liang, Wenmei; Ren, Tongming; Jing, Suhua; Lin, Juntang

2012-01-01

Highlights: ► Co-culture of Sertoli cells (SCs) with human umbilical cord mesenchymal stem cells (UCMSCs). ► Presence of SCs dramatically increased proliferation and migration of UCMSCs. ► Presence of SCs stimulated expression of Mdm2, Akt, CDC2, Cyclin D, CXCR4, MAPKs. -- Abstract: Human umbilical cord mesenchymal stem cells (hUCMSCs) have been recently used in transplant therapy. The proliferation and migration of MSCs are the determinants of the efficiency of MSC transplant therapy. Sertoli cells are a kind of “nurse” cells that support the development of sperm cells. Recent studies show that Sertoli cells promote proliferation of endothelial cells and neural stem cells in co-culture. We hypothesized that co-culture of UCMSCs with Sertoli cells may also promote proliferation and migration of UCMSCs. To examine this hypothesis, we isolated UCMSCs from human cords and Sertoli cells from mouse testes, and co-cultured them using a Transwell system. We found that UCMSCs exhibited strong proliferation ability and potential to differentiate to other cell lineages such as osteocytes and adipocytes. The presence of Sertoli cells in co-culture significantly enhanced the proliferation and migration potential of UCMSCs (P < 0.01). Moreover, these phenotypic changes were accompanied with upregulation of multiple genes involved in cell proliferation and migration including phospho-Akt, Mdm2, phospho-CDC2, Cyclin D1, Cyclin D3 as well as CXCR4, phospho-p44 MAPK and phospho-p38 MAPK. These findings indicate that Sertoli cells boost UCMSC proliferation and migration potential.

Co-culture with Sertoli cells promotes proliferation and migration of umbilical cord mesenchymal stem cells

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Zhang, Fenxi, E-mail: fxzhang0824@gmail.com [Department of Anatomy, Sanquan College, Xinxiang Medical University, Henan 453003, People' s Republic of China (China); Hong, Yan; Liang, Wenmei [Department of Histology and Embryology, Guiyang Medical University, Guizhou 550004, People' s Republic of China (China); Ren, Tongming [Department of Anatomy, Sanquan College, Xinxiang Medical University, Henan 453003, People' s Republic of China (China); Jing, Suhua [ICU Center, The Third Hospital of Xinxiang Medical University, Henan 453003, People' s Republic of China (China); Lin, Juntang [Stem Cell Center, Xinxiang Medical University, Henan 453003, People' s Republic of China (China)

2012-10-12

Highlights: Black-Right-Pointing-Pointer Co-culture of Sertoli cells (SCs) with human umbilical cord mesenchymal stem cells (UCMSCs). Black-Right-Pointing-Pointer Presence of SCs dramatically increased proliferation and migration of UCMSCs. Black-Right-Pointing-Pointer Presence of SCs stimulated expression of Mdm2, Akt, CDC2, Cyclin D, CXCR4, MAPKs. -- Abstract: Human umbilical cord mesenchymal stem cells (hUCMSCs) have been recently used in transplant therapy. The proliferation and migration of MSCs are the determinants of the efficiency of MSC transplant therapy. Sertoli cells are a kind of 'nurse' cells that support the development of sperm cells. Recent studies show that Sertoli cells promote proliferation of endothelial cells and neural stem cells in co-culture. We hypothesized that co-culture of UCMSCs with Sertoli cells may also promote proliferation and migration of UCMSCs. To examine this hypothesis, we isolated UCMSCs from human cords and Sertoli cells from mouse testes, and co-cultured them using a Transwell system. We found that UCMSCs exhibited strong proliferation ability and potential to differentiate to other cell lineages such as osteocytes and adipocytes. The presence of Sertoli cells in co-culture significantly enhanced the proliferation and migration potential of UCMSCs (P < 0.01). Moreover, these phenotypic changes were accompanied with upregulation of multiple genes involved in cell proliferation and migration including phospho-Akt, Mdm2, phospho-CDC2, Cyclin D1, Cyclin D3 as well as CXCR4, phospho-p44 MAPK and phospho-p38 MAPK. These findings indicate that Sertoli cells boost UCMSC proliferation and migration potential.

Impact of jamming on collective cell migration

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Nnetu, Kenechukwu David; Knorr, Melanie; Pawlizak, Steve; Fuhs, Thomas; Zink, Mareike; KäS, Josef A.

2012-02-01

Multi-cellular migration plays an important role in physiological processes such as embryogenesis, cancer metastasis and tissue repair. During migration, single cells undergo cycles of extension, adhesion and retraction resulting in morphological changes. In a confluent monolayer, there are inter-cellular interactions and crowding, however, the impact of these interactions on the dynamics and elasticity of the monolayer at the multi-cellular and single cell level is not well understood. Here we study the dynamics of a confluent epithelial monolayer by simultaneously measuring cell motion at the multi-cellular and single cell level for various cell densities and tensile elasticity. At the multi-cellular level, the system exhibited spatial kinetic transitions from isotropic to anisotropic migration on long times and the velocity of the monolayer decreased with increasing cell density. Moreover, the dynamics was spatially and temporally heterogeneous. Interestingly, the dynamics was also heterogeneous in wound-healing assays and the correlation length was fitted by compressed exponential. On the single cell scale, we observed transient caging effects with increasing cage rearrangement times as the system age due to an increase in density. Also, the density dependent elastic modulus of the monolayer scaled as a weak power law. Together, these findings suggest that caging effects at the single cell level initiates a slow and heterogeneous dynamics at the multi-cellular level which is similar to the glassy dynamics of deformable colloidal systems.

Platelets Inhibit Migration of Canine Osteosarcoma Cells.

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Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

2017-01-01

The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

Modeling collective cell migration in geometric confinement

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Tarle, Victoria; Gauquelin, Estelle; Vedula, S. R. K.; D'Alessandro, Joseph; Lim, C. T.; Ladoux, Benoit; Gov, Nir S.

2017-06-01

Monolayer expansion has generated great interest as a model system to study collective cell migration. During such an expansion the culture front often develops ‘fingers’, which we have recently modeled using a proposed feedback between the curvature of the monolayer’s leading edge and the outward motility of the edge cells. We show that this model is able to explain the puzzling observed increase of collective cellular migration speed of a monolayer expanding into thin stripes, as well as describe the behavior within different confining geometries that were recently observed in experiments. These comparisons give support to the model and emphasize the role played by the edge cells and the edge shape during collective cell motion.

The interplay between the hippocampus and the amygdala in regulating aberrant hippocampal neurogenesis during protracted abstinence from alcohol dependence

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Chitra D Mandyam

2013-06-01

Full Text Available The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems (e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal [HPA] hormonal levels, altered corticotropin-releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis.

Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP{sub swe}/PS1{sub {Delta}E9} transgenic mouse model of Alzheimer's disease

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Tang, Jun [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China); Department of Physiology, Third Military Medical University, Chongqing 400038 (China); Song, Min; Wang, Yanyan [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China); Fan, Xiaotang [Department of Histology and Embryology, Third Military Medical University, Chongqing 400038 (China); Xu, Haiwei, E-mail: haiweixu2001@yahoo.com.cn [Department of Physiology, Third Military Medical University, Chongqing 400038 (China); Bai, Yun, E-mail: baiyungene@gmail.com [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China)

2009-07-31

In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP{sub swe}/PS1{sub {Delta}E9} mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP{sub swe}/PS1{sub {Delta}E9} transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

Enrichment increases hippocampal neurogenesis independent of blood monocyte-derived microglia presence following high-dose total body irradiation.

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Ruitenberg, Marc J; Wells, Julia; Bartlett, Perry F; Harvey, Alan R; Vukovic, Jana

2017-06-01

Birth of new neurons in the hippocampus persists in the brain of adult mammals and critically underpins optimal learning and memory. The process of adult neurogenesis is significantly reduced following brain irradiation and this correlates with impaired cognitive function. In this study, we aimed to compare the long-term effects of two environmental paradigms (i.e. enriched environment and exercise) on adult neurogenesis following high-dose (10Gy) total body irradiation. When housed in standard (sedentary) conditions, irradiated mice revealed a long-lasting (up to 4 months) deficit in neurogenesis in the granule cell layer of the dentate gyrus, the region that harbors the neurogenic niche. This depressive effect of total body irradiation on adult neurogenesis was partially alleviated by exposure to enriched environment but not voluntary exercise, where mice were single-housed with unlimited access to a running wheel. Exposure to voluntary exercise, but not enriched environment, did lead to significant increases in microglia density in the granule cell layer of the hippocampus; our study shows that these changes result from local microglia proliferation rather than recruitment and infiltration of circulating Cx 3 cr1 +/gfp blood monocytes that subsequently differentiate into microglia-like cells. In summary, latent neural precursor cells remain present in the neurogenic niche of the adult hippocampus up to 8 weeks following high-dose total body irradiation. Environmental enrichment can partially restore the adult neurogenic process in this part of the brain following high-dose irradiation, and this was found to be independent of blood monocyte-derived microglia presence. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration

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Suzzi, Stefano; Vargas-Caballero, Mariana; Fransen, Nina L.; Al-Malki, Hussain; Cebrian-Silla, Arantxa; Garcia-Verdugo, Jose Manuel; Riecken, Kristoffer; Fehse, Boris; Perry, V. Hugh

2014-01-01

The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer’s disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases. PMID:24941947

ASIC PROTEINS REGULATE SMOOTH MUSCLE CELL MIGRATION

OpenAIRE

Grifoni, Samira C.; Jernigan, Nikki L.; Hamilton, Gina; Drummond, Heather A.

2007-01-01

The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated Epithelial Na+ Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration, however the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence indi...

Multidisciplinary approaches to understanding collective cell migration in developmental biology.

Science.gov (United States)

Schumacher, Linus J; Kulesa, Paul M; McLennan, Rebecca; Baker, Ruth E; Maini, Philip K

2016-06-01

Mathematical models are becoming increasingly integrated with experimental efforts in the study of biological systems. Collective cell migration in developmental biology is a particularly fruitful application area for the development of theoretical models to predict the behaviour of complex multicellular systems with many interacting parts. In this context, mathematical models provide a tool to assess the consistency of experimental observations with testable mechanistic hypotheses. In this review, we showcase examples from recent years of multidisciplinary investigations of neural crest cell migration. The neural crest model system has been used to study how collective migration of cell populations is shaped by cell-cell interactions, cell-environmental interactions and heterogeneity between cells. The wide range of emergent behaviours exhibited by neural crest cells in different embryonal locations and in different organisms helps us chart out the spectrum of collective cell migration. At the same time, this diversity in migratory characteristics highlights the need to reconcile or unify the array of currently hypothesized mechanisms through the next generation of experimental data and generalized theoretical descriptions. © 2016 The Authors.

Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis

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Alexandre A.S.F. Raposo

2015-03-01

Full Text Available The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program.

Migration of acute lymphoblastic leukemia cells into human bone marrow stroma.

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Makrynikola, V; Bianchi, A; Bradstock, K; Gottlieb, D; Hewson, J

1994-10-01

Most cases of acute lymphoblastic leukemia (ALL) arise from malignant transformation of B-cell precursors in the bone marrow. Recent studies have shown that normal and leukemic B-cell precursors bind to bone marrow stromal cells through the beta-1 integrins VLA-4 and VLA-5, thereby exposing early lymphoid cells to regulatory cytokines. It has been recently reported that the pre-B cell line NALM-6 is capable of migrating under layers of murine stromal cells in vitro (Miyake et al. J Cell Biol 1992;119:653-662). We have further analyzed leukemic cell motility using human bone marrow fibroblasts (BMF) as a stromal layer. The precursor-B ALL cell line NALM-6 rapidly adhered to BMF, and underwent migration or tunneling into BMF layers within 5 h, as demonstrated by light and electron microscopy, and confirmed by a chromium-labeling assay. Migration was also observed with the precursor-B ALL lines Reh and KM-3, with a T leukemia line RPMI-8402, the monocytic line U937, and the mature B line Daudi. In contrast, mature B (Raji), myeloid (K562, HL-60), and T lines (CCRF-CEM, MOLT-4) did not migrate. When cases of leukemia were analyzed, BMF migration was largely confined to precursor-B ALL, occurring in eight of 13 cases tested. Of other types of leukemia, migration was observed in one of four cases of T-ALL, but no evidence was seen in six acute myeloid leukemias and two patients with chronic lymphocytic leukemia. Only minimal migration into BMF was observed with purified sorted CD10+ CD19+ early B cells from normal adult marrow, while normal mature B lymphocytes from peripheral blood did not migrate. ALL migration was inhibited by monoclonal antibodies to the beta sub-unit of the VLA integrin family, and by a combination of antibodies to VLA-4 and VLA-5. Partial inhibition was also observed when leukemic cells were incubated with antibodies to VLA-4, VLA-5, or VLA-6 alone. In contrast, treatment of stromal cells with antibodies to vascular cell adhesion molecule or

High glucose-mediated oxidative stress impairs cell migration.

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Marcelo L Lamers

Full Text Available Deficient wound healing in diabetic patients is very frequent, but the cellular and molecular causes are poorly defined. In this study, we evaluate the hypothesis that high glucose concentrations inhibit cell migration. Using CHO.K1 cells, NIH-3T3 fibroblasts, mouse embryonic fibroblasts and primary skin fibroblasts from control and diabetic rats cultured in 5 mM D-glucose (low glucose, LG, 25 mM D-glucose (high glucose, HG or 25 mM L-glucose medium (osmotic control--OC, we analyzed the migration speed, protrusion stability, cell polarity, adhesion maturation and the activity of the small Rho GTPase Rac1. We also analyzed the effects of reactive oxygen species by incubating cells with the antioxidant N-Acetyl-Cysteine (NAC. We observed that HG conditions inhibited cell migration when compared to LG or OC. This inhibition resulted from impaired cell polarity, protrusion destabilization and inhibition of adhesion maturation. Conversely, Rac1 activity, which promotes protrusion and blocks adhesion maturation, was increased in HG conditions, thus providing a mechanistic basis for the HG phenotype. Most of the HG effects were partially or completely rescued by treatment with NAC. These findings demonstrate that HG impairs cell migration due to an increase in oxidative stress that causes polarity loss, deficient adhesion and protrusion. These alterations arise, in large part, from increased Rac1 activity and may contribute to the poor wound healing observed in diabetic patients.

Curcumin enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity.

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Suzhen Dong

Full Text Available BACKGROUND: Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. METHODOLOGY: We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. CONCLUSIONS: The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity.

Curcumin Enhances Neurogenesis and Cognition in Aged Rats: Implications for Transcriptional Interactions Related to Growth and Synaptic Plasticity

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Mitchell, E. Siobhan; Xiu, Jin; Tiwari, Jyoti K.; Hu, Yinghe; Cao, Xiaohua; Zhao, Zheng

2012-01-01

Background Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. Methodology We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. Conclusions The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity. PMID:22359574

Inhibition of Neurogenesis by Zika virus Infection.

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Ahmad, Fahim; Siddiqui, Amna; Kamal, Mohammad A; Sohrab, Sayed S

2018-02-01

The association between Zika virus infection and neurological disorder has raised urgent global alarm. The ongoing epidemic has triggered quick responses in the scientific community. The first case of Zika virus was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of travel-associated Zika virus infection have also been reported in the United States. Zika virus is primarily transmitted by mosquito belongs to the genus Aedes that are widely distributed throughout the world including the Southern United States. Additionally, the virus can also be transmitted from males to females by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and development of microcephaly in their unborn babies. This finding is a cause for grave concern since microcephaly is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicate that Zika virus infection affects the growth of fetal neural progenitor cells and cerebral neurons that results in malformation of cerebral cortex leading to microcephaly. Recently, it has been reported that Zika virus infection deregulates the signaling pathway of neuronal cell and inhibit the neurogenesis resulting into dementia. In this review we have discussed about the information about cellular and molecular mechanisms in neurodegeneration of human neuronal cells and inhibit the neurogenesis. Additionally, this information will be very helpful further not only in neuro-scientific research but also designing and development of management strategies for microcephaly and other mosquito borne disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Time-lapse cinematography of the capillary tube cell migration inhibition test.

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Bray, M A

1980-01-01

The kinetics of human and guinea pig cell migration inhibition have been studied using time-lapse cinematography of cells migrating from capillary tubes. Guinea pig and human cells exhibit markedly different kinetics in the absence of inhibitors. Specific antigen causes a dose-related inhibition of migration for up to 60 h using guinea pig cells and a peak of inhibition after 18 h using the human leucocyte system. The timing of measurement of maximum activity more critical for the latter test. The kinetics of lymphokine generation have been examined and the migration inhibitory activity of the plant mitogen (PHA), a Kurloff cell product and a continuous cell line supernatant have been compared with the inhibitory profiles of lymphokine preparations and specific antigen.

A role for adult TLX-positive neural stem cells in learning and behaviour.

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Zhang, Chun-Li; Zou, Yuhua; He, Weimin; Gage, Fred H; Evans, Ronald M

2008-02-21

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

Gamma radiation-induced Impairment of hippocampal neurogenesis, comparison of single and fractionated dose regimens

International Nuclear Information System (INIS)

Khoshbin khoshnazar, A. R; Jahanshahi, M; Azami, N. S

2012-01-01

Radiation therapy of the brain is associated with many consequences, including cognitive disorders. Pathogenesis of radiation induced cognitive disorder is not clear, but reduction of neurogenesis in hippocampus may be an underlying reason. 24 adult male rats entered to study. Radiation absorbed dose to midbrain was 10 Gy, delivered by routine cobalt radiotherapy machine which its output was measured 115.24 cGy/min. The rats were divided in four groups of sixes, including groups of control, single fraction 10 Gy, fractionated 10 Gy and finally anaesthesia sham group. Number of pyramidal nerve cells was counted in two regions of hippocampus formation (CA1 and CA3). The radiation could reduce the number of cells in two regions of hippocampus significantly (p=0.000). It seems fractionated 10 Gy irradiation to more efficient than single fraction, while role of anaesthesia drug should be cautiously assessed. Moreover the rate of neurogenesis reduction was determined the same in these regions of hippocampus meaning the same radiosensitivity of cells

Recent Advances on the Role of Neurogenesis in the Adult Brain: Therapeutic Potential in Parkinson's and Alzheimer's Diseases.

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Radad, Khaled; Moldzio, Rudolf; Al-Shraim, Mubarak; Kranner, Barbara; Krewenka, Christopher; Rausch, Wolf-Dieter

2017-01-01

Generation of nascent functional neurons from neural stem cells in the adult brain has recently become largely accepted by the neuroscience community. In adult mammals including humans, the process of neurogenesis has been well documented in two brain regions; the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. Some evidence has indicated neurogenesis in other regions of the adult mammalian brain such as the neocortex, cerebellum, striatum, amygdala and hypothalamus. These discoveries question a long standing dogma on nervous system regeneration and provide medical science with potential new strategies to harness the process of neurogenesis for treating neurological disabilities and neurodegenerative diseases. In this current review, we address the most recent advances on the role of neurogenesis in the adult brain and therapeutic potential in the two most common neurodegenerative disorders, Parkinson's and Alzheimer's diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Intranasal delivery of plasma and platelet growth factors using PRGF-Endoret system enhances neurogenesis in a mouse model of Alzheimer's disease.

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Eduardo Anitua

Full Text Available Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD induced by a combination of toxic amyloid-β peptide (Aβ and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret, an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1 mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU, doublecortin (DCX, and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD.

Intranasal delivery of plasma and platelet growth factors using PRGF-Endoret system enhances neurogenesis in a mouse model of Alzheimer's disease.

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Anitua, Eduardo; Pascual, Consuelo; Pérez-Gonzalez, Rocio; Antequera, Desiree; Padilla, Sabino; Orive, Gorka; Carro, Eva

2013-01-01

Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD.

Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells.

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Kishimoto, Seishi; Muramatsu, Mayumi; Gokoh, Maiko; Oka, Saori; Waku, Keizo; Sugiura, Takayuki

2005-02-01

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays important physiological roles in several mammalian tissues and cells, yet the details remain ambiguous. In this study, we first examined the effects of 2-arachidonoylglycerol on the motility of human natural killer cells. We found that 2-arachidonoylglycerol induces the migration of KHYG-1 cells (a natural killer leukemia cell line) and human peripheral blood natural killer cells. The migration of natural killer cells induced by 2-arachidonoylglycerol was abolished by treating the cells with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the 2-arachidonoylglycerol-induced migration. In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, did not induce the migration. Delta9-tetrahydrocannabinol, a major psychoactive constituent of marijuana, also failed to induce the migration; instead, the addition of delta9-tetrahydrocannabinol together with 2-arachidonoylglycerol abolished the migration induced by 2-arachidonoylglycerol. It is conceivable that the endogenous ligand for the cannabinoid receptor, that is, 2-arachidonoylglycerol, affects natural killer cell functions such as migration, thereby contributing to the host-defense mechanism against infectious viruses and tumor cells.

SOX9 as a Predictor for Neurogenesis Potentiality of Amniotic Fluid Stem Cells

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Wei, Pei-Cih; Chao, Angel; Peng, Hsiu-Huei; Chao, An-Shine; Chang, Yao-Lung; Chang, Shuenn-Dyh; Wang, Hsin-Shih; Chang, Yu-Jen; Tsai, Ming-Song; Sieber, Martin; Chen, Hua-Chien; Chen, Shu-Jen; Lee, Yun-Shien

2014-01-01

Preclinical studies of amniotic fluid-derived cell therapy have been successful in the research of neurodegenerative diseases, peripheral nerve injury, spinal cord injury, and brain ischemia. Transplantation of human amniotic fluid stem cells (AFSCs) into rat brain ventricles has shown improvement in symptoms of Parkinson's disease and also highlighted the minimal immune rejection risk of AFSCs, even between species. Although AFSCs appeared to be a promising resource for cell-based regenerative therapy, AFSCs contain a heterogeneous pool of distinct cell types, rendering each preparation of AFSCs unique. Identification of predictive markers for neuron-prone AFSCs is necessary before such stem cell-based therapeutics can become a reality. In an attempt to identify markers of AFSCs to predict their ability for neurogenesis, we performed a two-phase study. In the discovery phase of 23 AFSCs, we tested ZNF521/Zfp521, OCT6, SOX1, SOX2, SOX3, and SOX9 as predictive markers of AFSCs for neural differentiation. In the validation phase, the efficacy of these predictive markers was tested in independent sets of 18 AFSCs and 14 dental pulp stem cells (DPSCs). We found that high expression of SOX9 in AFSCs is associated with good neurogenetic ability, and these positive correlations were confirmed in independent sets of AFSCs and DPSCs. Furthermore, knockdown of SOX9 in AFSCs inhibited their neuronal differentiation. In conclusion, the discovery of SOX9 as a predictive marker for neuron-prone AFSCs could expedite the selection of useful clones for regenerative medicine, in particular, in neurological diseases and injuries. PMID:25154783

Hippocampal Astrocytes in Migrating and Wintering Semipalmated Sandpiper Calidris pusilla.

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Carvalho-Paulo, Dario; de Morais Magalhães, Nara G; de Almeida Miranda, Diego; Diniz, Daniel G; Henrique, Ediely P; Moraes, Isis A M; Pereira, Patrick D C; de Melo, Mauro A D; de Lima, Camila M; de Oliveira, Marcus A; Guerreiro-Diniz, Cristovam; Sherry, David F; Diniz, Cristovam W P

2017-01-01

Seasonal migratory birds return to the same breeding and wintering grounds year after year, and migratory long-distance shorebirds are good examples of this. These tasks require learning and long-term spatial memory abilities that are integrated into a navigational system for repeatedly locating breeding, wintering, and stopover sites. Previous investigations focused on the neurobiological basis of hippocampal plasticity and numerical estimates of hippocampal neurogenesis in birds but only a few studies investigated potential contributions of glial cells to hippocampal-dependent tasks related to migration. Here we hypothesized that the astrocytes of migrating and wintering birds may exhibit significant morphological and numerical differences connected to the long-distance flight. We used as a model the semipalmated sandpiper Calidris pusilla , that migrates from northern Canada and Alaska to South America. Before the transatlantic non-stop long-distance component of their flight, the birds make a stopover at the Bay of Fundy in Canada. To test our hypothesis, we estimated total numbers and compared the three-dimensional (3-D) morphological features of adult C. pusilla astrocytes captured in the Bay of Fundy ( n = 249 cells) with those from birds captured in the coastal region of Bragança, Brazil, during the wintering period ( n = 250 cells). Optical fractionator was used to estimate the number of astrocytes and for 3-D reconstructions we used hierarchical cluster analysis. Both morphological phenotypes showed reduced morphological complexity after the long-distance non-stop flight, but the reduction in complexity was much greater in Type I than in Type II astrocytes. Coherently, we also found a significant reduction in the total number of astrocytes after the transatlantic flight. Taken together these findings suggest that the long-distance non-stop flight altered significantly the astrocytes population and that morphologically distinct astrocytes may play

Hippocampal Astrocytes in Migrating and Wintering Semipalmated Sandpiper Calidris pusilla

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Dario Carvalho-Paulo

2018-01-01

Full Text Available Seasonal migratory birds return to the same breeding and wintering grounds year after year, and migratory long-distance shorebirds are good examples of this. These tasks require learning and long-term spatial memory abilities that are integrated into a navigational system for repeatedly locating breeding, wintering, and stopover sites. Previous investigations focused on the neurobiological basis of hippocampal plasticity and numerical estimates of hippocampal neurogenesis in birds but only a few studies investigated potential contributions of glial cells to hippocampal-dependent tasks related to migration. Here we hypothesized that the astrocytes of migrating and wintering birds may exhibit significant morphological and numerical differences connected to the long-distance flight. We used as a model the semipalmated sandpiper Calidris pusilla, that migrates from northern Canada and Alaska to South America. Before the transatlantic non-stop long-distance component of their flight, the birds make a stopover at the Bay of Fundy in Canada. To test our hypothesis, we estimated total numbers and compared the three-dimensional (3-D morphological features of adult C. pusilla astrocytes captured in the Bay of Fundy (n = 249 cells with those from birds captured in the coastal region of Bragança, Brazil, during the wintering period (n = 250 cells. Optical fractionator was used to estimate the number of astrocytes and for 3-D reconstructions we used hierarchical cluster analysis. Both morphological phenotypes showed reduced morphological complexity after the long-distance non-stop flight, but the reduction in complexity was much greater in Type I than in Type II astrocytes. Coherently, we also found a significant reduction in the total number of astrocytes after the transatlantic flight. Taken together these findings suggest that the long-distance non-stop flight altered significantly the astrocytes population and that morphologically distinct astrocytes

Paxillin: a crossroad in pathological cell migration

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Ana María López-Colomé

2017-02-01

Full Text Available Abstract Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.

Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

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He Liu

2016-01-01

Full Text Available Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain tumors.

Adult Neurogenesis in Sheep: Characterization and Contribution to Reproduction and Behavior

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Lévy, Frederic; Batailler, Martine; Meurisse, Maryse; Migaud, Martine

2017-01-01

Sheep have many advantages to study neurogenesis in comparison to the well-known rodent models. Their development and life expectancy are relatively long and they possess a gyrencephalic brain. Sheep are also seasonal breeders, a characteristic that allows studying the involvement of hypothalamic neurogenesis in the control of seasonal reproduction. Sheep are also able to individually recognize their conspecifics and develop selective and lasting bonds. Adult olfactory neurogenesis could be adapted to social behavior by supporting recognition of conspecifics. The present review reveals the distinctive features of the hippocampal, olfactory, and hypothalamic neurogenesis in sheep. In particular, the organization of the subventricular zone and the dynamic of neuronal maturation differs from that of rodents. In addition, we show that various physiological conditions, such as seasonal reproduction, gestation, and lactation differently modulate these three neurogenic niches. Last, we discuss recent evidence indicating that hypothalamic neurogenesis acts as an important regulator of the seasonal control of reproduction and that olfactory neurogenesis could be involved in odor processing in the context of maternal behavior. PMID:29109674

LRRK2: an éminence grise of Wnt-mediated neurogenesis?

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Daniel C Berwick

2013-05-01

Full Text Available The importance of Leucine-Rich Repeat Kinase 2 (LRRK2 to mature neurons is well-established, since mutations in PARK8, the gene encoding LRRK2, are the most common known cause of Parkinson’s disease. Nonetheless, despite the LRRK2 knockout mouse having no overt neurodevelopmental defect, numerous lines of in vitro data point towards a central role for this protein in neurogenesis. Roles for LRRK2 have been described in many key processes, including neurite outgrowth and the regulation of microtubule dynamics. Moreover, LRRK2 has been implicated in cell cycle control, suggesting additional roles in neurogenesis that precede terminal differentiation. However, we contend that the suggested function of LRRK2 as a scaffolding protein at the heart of numerous Wnt signaling cascades provides the most tantalizing link to neurogenesis in the developing brain. Numerous lines of evidence show a critical requirement for multiple Wnt pathways in the development of certain brain regions, not least the dopaminergic neurons of the ventral mid-brain. In conclusion, these observations indicate a function of LRRK2 as a subtle yet critical mediator of the action of Wnt ligands on developing neurons. We suggest that LRRK2 loss- or gain-of-function are likely modifiers of developmental phenotypes seen in animal models of Wnt signaling deregulation, a hypothesis that can be tested by cross-breeding relevant genetically modified experimental strains.

A PDMS Device Coupled with Culture Dish for In Vitro Cell Migration Assay.

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Lv, Xiaoqing; Geng, Zhaoxin; Fan, Zhiyuan; Wang, Shicai; Pei, WeiHua; Chen, Hongda

2018-04-30

Cell migration and invasion are important factors during tumor progression and metastasis. Wound-healing assay and the Boyden chamber assay are efficient tools to investigate tumor development because both of them could be applied to measure cell migration rate. Therefore, a simple and integrated polydimethylsiloxane (PDMS) device was developed for cell migration assay, which could perform quantitative evaluation of cell migration behaviors, especially for the wound-healing assay. The integrated device was composed of three units, which included cell culture dish, PDMS chamber, and wound generation mold. The PDMS chamber was integrated with cell culture chamber and could perform six experiments under different conditions of stimuli simultaneously. To verify the function of this device, it was utilized to explore the tumor cell migration behaviors under different concentrations of fetal bovine serum (FBS) and transforming growth factor (TGF-β) at different time points. This device has the unique capability to create the "wound" area in parallel during cell migration assay and provides a simple and efficient platform for investigating cell migration assay in biomedical application.

Impact of tumor cell cytoskeleton organization on invasiveness and migration: a microchannel-based approach.

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Claudio G Rolli

2010-01-01

Full Text Available Cell migration is a fundamental feature of the interaction of cells with their surrounding. The cell's stiffness and ability to deform itself are two major characteristics that rule migration behavior especially in three-dimensional tissue. We simulate this situation making use of a micro-fabricated migration chip to test the active invasive behavior of pancreatic cancer cells (Panc-1 into narrow channels. At a channel width of 7 microm cell migration through the channels was significantly impeded due to size exclusion. A striking increase in cell invasiveness was observed once the cells were treated with the bioactive lipid sphingosylphosphorylcholine (SPC that leads to a reorganization of the cell's keratin network, an enhancement of the cell's deformability, and also an increase in the cell's migration speed on flat surfaces. The migration speed of the highly deformed cells inside the channels was three times higher than of cells on flat substrates but was not affected upon SPC treatment. Cells inside the channels migrated predominantly by smooth sliding while maintaining constant cell length. In contrast, cells on adhesion mediating narrow lines moved in a stepwise way, characterized by fluctuations in cell length. Taken together, with our migration chip we demonstrate that the dimensionality of the environment strongly affects the migration phenotype and we suggest that the spatial cytoskeletal keratin organization correlates with the tumor cell's invasive potential.

Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration.

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Somogyi, Kálmán; Rørth, Pernille

2004-07-01

Cells migrating through a tissue exert force via their cytoskeleton and are themselves subject to tension, but the effects of physical forces on cell behavior in vivo are poorly understood. Border cell migration during Drosophila oogenesis is a useful model for invasive cell movement. We report that this migration requires the activity of the transcriptional factor serum response factor (SRF) and its cofactor MAL-D and present evidence that nuclear accumulation of MAL-D is induced by cell stretching. Border cells that cannot migrate lack nuclear MAL-D but can accumulate it if they are pulled by other migrating cells. Like mammalian MAL, MAL-D also responds to activated Diaphanous, which affects actin dynamics. MAL-D/SRF activity is required to build a robust actin cytoskeleton in the migrating cells; mutant cells break apart when initiating migration. Thus, tension-induced MAL-D activity may provide a feedback mechanism for enhancing cytoskeletal strength during invasive migration.

Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma

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Ramos, Grasieli de Oliveira; Bernardi, Lisiane; Lauxen, Isabel; Sant’Ana Filho, Manoel; Horwitz, Alan Rick; Lamers, Marcelo Lazzaron

2016-01-01

Cell migration is regulated by adhesion to the extracellular matrix (ECM) through integrins and activation of small RhoGTPases, such as RhoA and Rac1, resulting in changes to actomyosin organization. During invasion, epithelial-derived tumor cells switch from laminin-enriched basal membrane to collagen and fibronectin-enriched connective tissue. How this switch affects the tumor migration is still unclear. We tested the hypothesis that ECM dictates the invasiveness of Oral Squamous Cell Carcinoma (OSCC). We analyzed the migratory properties of two OSCC lines, a low invasive cell line with high e-cadherin levels (Linv/HE-cad) or a highly invasive cell line with low e-cadherin levels (Hinv/LE-cad), plated on different ECM components. Compared to laminin, fibronectin induced non-directional collective migration and decreased RhoA activity in Linv/HE-cad OSCC. For Hinv/LE-cad OSCC, fibronectin increased Rac1 activity and induced smaller adhesions, resulting in a fast single cell migration in both 2D and 3D environments. Consistent with these observations, human OSCC biopsies exhibited similar changes in cell-ECM adhesion distribution at the invasive front of the tumor, where cells encounter fibronectin. Our results indicate that ECM composition might induce a switch from collective to single cell migration according to tumor invasiveness due to changes in cell-ECM adhesion and the resulting signaling pathways that alter actomyosin organization. PMID:26978651

Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma.

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Grasieli de Oliveira Ramos

Full Text Available Cell migration is regulated by adhesion to the extracellular matrix (ECM through integrins and activation of small RhoGTPases, such as RhoA and Rac1, resulting in changes to actomyosin organization. During invasion, epithelial-derived tumor cells switch from laminin-enriched basal membrane to collagen and fibronectin-enriched connective tissue. How this switch affects the tumor migration is still unclear. We tested the hypothesis that ECM dictates the invasiveness of Oral Squamous Cell Carcinoma (OSCC. We analyzed the migratory properties of two OSCC lines, a low invasive cell line with high e-cadherin levels (Linv/HE-cad or a highly invasive cell line with low e-cadherin levels (Hinv/LE-cad, plated on different ECM components. Compared to laminin, fibronectin induced non-directional collective migration and decreased RhoA activity in Linv/HE-cad OSCC. For Hinv/LE-cad OSCC, fibronectin increased Rac1 activity and induced smaller adhesions, resulting in a fast single cell migration in both 2D and 3D environments. Consistent with these observations, human OSCC biopsies exhibited similar changes in cell-ECM adhesion distribution at the invasive front of the tumor, where cells encounter fibronectin. Our results indicate that ECM composition might induce a switch from collective to single cell migration according to tumor invasiveness due to changes in cell-ECM adhesion and the resulting signaling pathways that alter actomyosin organization.

Proteolytic Enzymes Clustered in Specialized Plasma-Membrane Domains Drive Endothelial Cells' Migration.

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Monica Salamone

Full Text Available In vitro cultured endothelial cells forming a continuous monolayer establish stable cell-cell contacts and acquire a "resting" phenotype; on the other hand, when growing in sparse conditions these cells acquire a migratory phenotype and invade the empty area of the culture. Culturing cells in different conditions, we compared expression and clustering of proteolytic enzymes in cells having migratory versus stationary behavior. In order to observe resting and migrating cells in the same microscopic field, a continuous cell monolayer was wounded. Increased expression of proteolytic enzymes was evident in cell membranes of migrating cells especially at sprouting sites and in shed membrane vesicles. Gelatin zymography and western blotting analyses confirmed that in migrating cells, expression of membrane-bound and of vesicle-associated proteolytic enzymes are increased. The enzymes concerned include MMP-2, MMP-9, MT1-MMP, seprase, DPP4 (DiPeptidyl Peptidase 4 and uPA. Shed membrane vesicles were shown to exert degradative activity on ECM components and produce substrates facilitating cell migration. Vesicles shed by migrating cells degraded ECM components at an increased rate; as a result their effect on cell migration was amplified. Inhibiting either Matrix Metallo Proteases (MMPs or Serine Integral Membrane Peptidases (SIMPs caused a decrease in the stimulatory effect of vesicles, inhibiting the spontaneous migratory activity of cells; a similar result was also obtained when a monoclonal antibody acting on DPP4 was tested. We conclude that proteolytic enzymes have a synergistic stimulatory effect on cell migration and that their clustering probably facilitates the proteolytic activation cascades needed to produce maximal degradative activity on cell substrates during the angiogenic process.

Proteolytic Enzymes Clustered in Specialized Plasma-Membrane Domains Drive Endothelial Cells' Migration.

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Salamone, Monica; Carfì Pavia, Francesco; Ghersi, Giulio

2016-01-01

In vitro cultured endothelial cells forming a continuous monolayer establish stable cell-cell contacts and acquire a "resting" phenotype; on the other hand, when growing in sparse conditions these cells acquire a migratory phenotype and invade the empty area of the culture. Culturing cells in different conditions, we compared expression and clustering of proteolytic enzymes in cells having migratory versus stationary behavior. In order to observe resting and migrating cells in the same microscopic field, a continuous cell monolayer was wounded. Increased expression of proteolytic enzymes was evident in cell membranes of migrating cells especially at sprouting sites and in shed membrane vesicles. Gelatin zymography and western blotting analyses confirmed that in migrating cells, expression of membrane-bound and of vesicle-associated proteolytic enzymes are increased. The enzymes concerned include MMP-2, MMP-9, MT1-MMP, seprase, DPP4 (DiPeptidyl Peptidase 4) and uPA. Shed membrane vesicles were shown to exert degradative activity on ECM components and produce substrates facilitating cell migration. Vesicles shed by migrating cells degraded ECM components at an increased rate; as a result their effect on cell migration was amplified. Inhibiting either Matrix Metallo Proteases (MMPs) or Serine Integral Membrane Peptidases (SIMPs) caused a decrease in the stimulatory effect of vesicles, inhibiting the spontaneous migratory activity of cells; a similar result was also obtained when a monoclonal antibody acting on DPP4 was tested. We conclude that proteolytic enzymes have a synergistic stimulatory effect on cell migration and that their clustering probably facilitates the proteolytic activation cascades needed to produce maximal degradative activity on cell substrates during the angiogenic process.

Hematopoietic stem cell migration and proliferation after Partial body irradiation

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Murata, Takashi; Utsumi, Makoto; Hotta, Tomomitsu; Yamada, Hideo

1983-01-01

Stem cell migration in hematopoietic recovery after partial body irradiation was investigated with special emphasis on the comparative roles of the bone marrow and the spleen. The number of CFU-S in circulation declined rapidly and reached zero within a day after irradiation, thereafter it increased gradually. This finding suggests the presence of two different phases of stem cell migration. One is a rapid migrating phase in which stem cells are released rapidly within a day after irradiation, and the other is a slow migrating phase. The result of split doses of local body irradiation experiments implicated a role for the spleen distinct from that of the bone marrow in the preferential distribution of stem cells early after irradiation. The cell kinetic study showed that the proliferation of CFU-S occurred actively in irradiated bone marrow and the spleens as compared to that in unirradiated control. But on Day 7 and on Day 10 after irradiation, the proliferation of CFU-S in shielded bone marrow did not occur as actively as those in irradiated areas. The results of our present studies suggest that the spleen is not only the storage pools of migrating stem cells but also the main site of active proliferation of CFU-S in the early period of hematopoietic regeneration. (author)

Modeling and predictions of biphasic mechanosensitive cell migration altered by cell-intrinsic properties and matrix confinement.

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Pathak, Amit

2018-04-12

Motile cells sense the stiffness of their extracellular matrix (ECM) through adhesions and respond by modulating the generated forces, which in turn lead to varying mechanosensitive migration phenotypes. Through modeling and experiments, cell migration speed is known to vary with matrix stiffness in a biphasic manner, with optimal motility at an intermediate stiffness. Here, we present a two-dimensional cell model defined by nodes and elements, integrated with subcellular modeling components corresponding to mechanotransductive adhesion formation, force generation, protrusions and node displacement. On 2D matrices, our calculations reproduce the classic biphasic dependence of migration speed on matrix stiffness and predict that cell types with higher force-generating ability do not slow down on very stiff matrices, thus disabling the biphasic response. We also predict that cell types defined by lower number of total receptors require stiffer matrices for optimal motility, which also limits the biphasic response. For a cell type with robust biphasic migration on 2D surface, simulations in channel-like confined environments of varying width and height predict faster migration in more confined matrices. Simulations performed in shallower channels predict that the biphasic mechanosensitive cell migration response is more robust on 2D micro-patterns as compared to the channel-like 3D confinement. Thus, variations in the dimensionality of matrix confinement alters the way migratory cells sense and respond to the matrix stiffness. Our calculations reveal new phenotypes of stiffness- and topography-sensitive cell migration that critically depend on both cell-intrinsic and matrix properties. These predictions may inform our understanding of various mechanosensitive modes of cell motility that could enable tumor invasion through topographically heterogeneous microenvironments. © 2018 IOP Publishing Ltd.

Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain.

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Manohar B Mutnal

2011-01-01

Full Text Available Congenital cytomegalovirus (CMV brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV and the pattern of injury to the developing brain.We used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection.MCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons.

Cell Migration According to Shape of Graphene Oxide Micropatterns

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Sung Eun Kim

2016-10-01

Full Text Available Photolithography is a unique process that can effectively manufacture micro/nano-sized patterns on various substrates. On the other hand, the meniscus-dragging deposition (MDD process can produce a uniform surface of the substrate. Graphene oxide (GO is the oxidized form of graphene that has high hydrophilicity and protein absorption. It is widely used in biomedical fields such as drug delivery, regenerative medicine, and tissue engineering. Herein, we fabricated uniform GO micropatterns via MDD and photolithography. The physicochemical properties of the GO micropatterns were characterized by atomic force microscopy (AFM, scanning electron microscopy (SEM, and Raman spectroscopy. Furthermore, cell migration on the GO micropatterns was investigated, and the difference in cell migration on triangle and square GO micropatterns was examined for their effects on cell migration. Our results demonstrated that the GO micropatterns with a desired shape can be finely fabricated via MDD and photolithography. Moreover, it was revealed that the shape of GO micropatterns plays a crucial role in cell migration distance, speed, and directionality. Therefore, our findings suggest that the GO micropatterns can serve as a promising biofunctional platform and cell-guiding substrate for applications to bioelectric devices, cell-on-a-chip, and tissue engineering scaffolds.

Laser-photophoretic migration and fractionation of human blood cells

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Monjushiro, Hideaki; Tanahashi, Yuko; Watarai, Hitoshi

2013-01-01

Graphical abstract: -- Highlights: •RBCs were migrated faster than WBCs and blood pellets by laser photophoresis. •Photophoretic efficiency of RBC and WBC was simulated by the Mie scattering theory. •Spontaneous orientation of RBC parallel to the migration direction was elucidated. •Laser photophoretic separation of RBC and WBC was possible in a tip flow system. -- Abstract: Laser photophoretic migration behavior of human blood cells in saline solution was investigated under the irradiation of Nd:YAG laser beam (532 nm) in the absence and the presence of the flow in a fused silica capillary. Red blood cells (RBC) were migrated faster than white blood cells (WBC) and blood pellets to the direction of propagation of laser light. The observed photophoretic velocity of RBC was about 11 times faster than those of others. This was understood from the larger photophoretic efficiency of RBC than that of WBC, which was simulated based on the Mie scattering theory. Furthermore, it was found that, during the photophoretic migration, RBCs spontaneously orientated parallel to the migration direction so as to reduce the drag force. Finally, it was demonstrated that RBC and WBC were separated in a micro-channel flow system by the laser photophoresis

Laser-photophoretic migration and fractionation of human blood cells

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Monjushiro, Hideaki; Tanahashi, Yuko; Watarai, Hitoshi, E-mail: watarai@chem.sci.osaka-u.ac.jp

2013-05-13

Graphical abstract: -- Highlights: •RBCs were migrated faster than WBCs and blood pellets by laser photophoresis. •Photophoretic efficiency of RBC and WBC was simulated by the Mie scattering theory. •Spontaneous orientation of RBC parallel to the migration direction was elucidated. •Laser photophoretic separation of RBC and WBC was possible in a tip flow system. -- Abstract: Laser photophoretic migration behavior of human blood cells in saline solution was investigated under the irradiation of Nd:YAG laser beam (532 nm) in the absence and the presence of the flow in a fused silica capillary. Red blood cells (RBC) were migrated faster than white blood cells (WBC) and blood pellets to the direction of propagation of laser light. The observed photophoretic velocity of RBC was about 11 times faster than those of others. This was understood from the larger photophoretic efficiency of RBC than that of WBC, which was simulated based on the Mie scattering theory. Furthermore, it was found that, during the photophoretic migration, RBCs spontaneously orientated parallel to the migration direction so as to reduce the drag force. Finally, it was demonstrated that RBC and WBC were separated in a micro-channel flow system by the laser photophoresis.

Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes

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Chris L. Smith

2016-06-01

Full Text Available Glioblastoma multiforme is a heterogeneous and infiltrative cancer with dismal prognosis. Studying the migratory behavior of tumor-derived cell populations can be informative, but it places a high premium on the precision of in vitro methods and the relevance of in vivo conditions. In particular, the analysis of 2D cell migration may not reflect invasion into 3D extracellular matrices in vivo. Here, we describe a method that allows time-resolved studies of primary cell migration with single-cell resolution on a fibrillar surface that closely mimics in vivo 3D migration. We used this platform to screen 14 patient-derived glioblastoma samples. We observed that the migratory phenotype of a subset of cells in response to platelet-derived growth factor was highly predictive of tumor location and recurrence in the clinic. Therefore, migratory phenotypic classifiers analyzed at the single-cell level in a patient-specific way can provide high diagnostic and prognostic value for invasive cancers.

Emergent patterns of collective cell migration under tubular confinement.

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Xi, Wang; Sonam, Surabhi; Beng Saw, Thuan; Ladoux, Benoit; Teck Lim, Chwee

2017-11-15

Collective epithelial behaviors are essential for the development of lumens in organs. However, conventional assays of planar systems fail to replicate cell cohorts of tubular structures that advance in concerted ways on out-of-plane curved and confined surfaces, such as ductal elongation in vivo. Here, we mimic such coordinated tissue migration by forming lumens of epithelial cell sheets inside microtubes of 1-10 cell lengths in diameter. We show that these cell tubes reproduce the physiological apical-basal polarity, and have actin alignment, cell orientation, tissue organization, and migration modes that depend on the extent of tubular confinement and/or curvature. In contrast to flat constraint, the cell sheets in a highly constricted smaller microtube demonstrate slow motion with periodic relaxation, but fast overall movement in large microtubes. Altogether, our findings provide insights into the emerging migratory modes for epithelial migration and growth under tubular confinement, which are reminiscent of the in vivo scenario.

Social isolation disrupts hippocampal neurogenesis in young non-human primates

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Simone M Cinini

2014-03-01

Full Text Available Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for one or three weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming - an indicative of attenuation of tension - was reduced among isolated marmosets. These results were consistent with increased cortisol levels after one and three weeks of isolation. After social isolation (one or three weeks, reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling. Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.

Food restriction reduces neurogenesis in the avian hippocampal formation.

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Barbara-Anne Robertson

Full Text Available The mammalian hippocampus is particularly vulnerable to chronic stress. Adult neurogenesis in the dentate gyrus is suppressed by chronic stress and by administration of glucocorticoid hormones. Post-natal and adult neurogenesis are present in the avian hippocampal formation as well, but much less is known about its sensitivity to chronic stressors. In this study, we investigate this question in a commercial bird model: the broiler breeder chicken. Commercial broiler breeders are food restricted during development to manipulate their growth curve and to avoid negative health outcomes, including obesity and poor reproductive performance. Beyond knowing that these chickens are healthier than fully-fed birds and that they have a high motivation to eat, little is known about how food restriction impacts the animals' physiology. Chickens were kept on a commercial food-restricted diet during the first 12 weeks of life, or released from this restriction by feeding them ad libitum from weeks 7-12 of life. To test the hypothesis that chronic food restriction decreases the production of new neurons (neurogenesis in the hippocampal formation, the cell proliferation marker bromodeoxyuridine was injected one week prior to tissue collection. Corticosterone levels in blood plasma were elevated during food restriction, even though molecular markers of hypothalamic-pituitary-adrenal axis activation did not differ between the treatments. The density of new hippocampal neurons was significantly reduced in the food-restricted condition, as compared to chickens fed ad libitum, similar to findings in rats at a similar developmental stage. Food restriction did not affect hippocampal volume or the total number of neurons. These findings indicate that in birds, like in mammals, reduction in hippocampal neurogenesis is associated with chronically elevated corticosterone levels, and therefore potentially with chronic stress in general. This finding is consistent with the

The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo.

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Rella, Lorenzo; Fernandes Póvoa, Euclides E; Korswagen, Hendrik C

2016-04-01

During development, cell migration plays a central role in the formation of tissues and organs. Understanding the molecular mechanisms that drive and control these migrations is a key challenge in developmental biology that will provide important insights into disease processes, including cancer cell metastasis. In this article, we discuss the Caenorhabditis elegans Q neuroblasts and their descendants as a tool to study cell migration at single-cell resolution in vivo. The highly stereotypical migration of these cells provides a powerful system to study the dynamic cytoskeletal processes that drive migration as well as the evolutionarily conserved signaling pathways (including different Wnt signaling cascades) that guide the cells along their specific trajectories. Here, we provide an overview of what is currently known about Q neuroblast migration and highlight the live-cell imaging, genome editing, and quantitative gene expression techniques that have been developed to study this process. © 2016 Wiley Periodicals, Inc.

Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats

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Cesar A. Acevedo-Triana

2017-05-01

Full Text Available Background Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis, causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. Methods An experimental design with two groups was developed: the experimental group (n = 12 was subject to a forced exercise program for five days, whereas the control group (n = 9 stayed in the home cage. Six to eight weeks after training, the rats’ working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. Results No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding, or in the levels of BrdU positive cells. Discussion Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level.

Tre1, a G protein-coupled receptor, directs transepithelial migration of Drosophila germ cells.

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Prabhat S Kunwar

2003-12-01

Full Text Available In most organisms, germ cells are formed distant from the somatic part of the gonad and thus have to migrate along and through a variety of tissues to reach the gonad. Transepithelial migration through the posterior midgut (PMG is the first active step during Drosophila germ cell migration. Here we report the identification of a novel G protein-coupled receptor (GPCR, Tre1, that is essential for this migration step. Maternal tre1 RNA is localized to germ cells, and tre1 is required cell autonomously in germ cells. In tre1 mutant embryos, most germ cells do not exit the PMG. The few germ cells that do leave the midgut early migrate normally to the gonad, suggesting that this gene is specifically required for transepithelial migration and that mutant germ cells are still able to recognize other guidance cues. Additionally, inhibiting small Rho GTPases in germ cells affects transepithelial migration, suggesting that Tre1 signals through Rho1. We propose that Tre1 acts in a manner similar to chemokine receptors required during transepithelial migration of leukocytes, implying an evolutionarily conserved mechanism of transepithelial migration. Recently, the chemokine receptor CXCR4 was shown to direct migration in vertebrate germ cells. Thus, germ cells may more generally use GPCR signaling to navigate the embryo toward their target.

A pilgrim's progress: Seeking meaning in primordial germ cell migration.

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Cantú, Andrea V; Laird, Diana J

2017-10-01

Comparative studies of primordial germ cell (PGC) development across organisms in many phyla reveal surprising diversity in the route of migration, timing and underlying molecular mechanisms, suggesting that the process of migration itself is conserved. However, beyond the perfunctory transport of cellular precursors to their later arising home of the gonads, does PGC migration serve a function? Here we propose that the process of migration plays an additional role in quality control, by eliminating PGCs incapable of completing migration as well as through mechanisms that favor PGCs capable of responding appropriately to migration cues. Focusing on PGCs in mice, we explore evidence for a selective capacity of migration, considering the tandem regulation of proliferation and migration, cell-intrinsic and extrinsic control, the potential for tumors derived from failed PGC migrants, the potential mechanisms by which migratory PGCs vary in their cellular behaviors, and corresponding effects on development. We discuss the implications of a selective role of PGC migration for in vitro gametogenesis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Intranasal Delivery of Plasma and Platelet Growth Factors Using PRGF-Endoret System Enhances Neurogenesis in a Mouse Model of Alzheimer’s Disease

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Anitua, Eduardo; Pascual, Consuelo; Pérez-Gonzalez, Rocio; Antequera, Desiree; Padilla, Sabino; Orive, Gorka; Carro, Eva

2013-01-01

Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer’s disease (AD) induced by a combination of toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD. PMID:24069173

HGF and c-Met Interaction Promotes Migration in Human Chondrosarcoma Cells

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Tsou, Hsi-Kai; Chen, Hsien-Te; Hung, Ya-Huey; Chang, Chia-Hao; Li, Te-Mao; Fong, Yi-Chin; Tang, Chih-Hsin

2013-01-01

Chondrosarcoma is a type of highly malignant tumor with a potent capacity for local invasion and causing distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Hepatocyte growth factor (HGF) has been demonstrated to stimulate cancer proliferation, migration, and metastasis. However, the effect of HGF on migration activity of human chondrosarcoma cells is not well known. Here, we found that human chondrosarcoma tissues demonstrated significant expression of HGF, which was higher than that in normal cartilage. We also found that HGF increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. c-Met inhibitor and siRNA reduced HGF-increased cell migration and MMP-2 expression. HGF treatment resulted in activation of the phosphatidylinositol 3′-kinase (PI3K)/Akt/PKCδ/NF-κB pathway, and HGF-induced expression of MMP-2 and cell migration was inhibited by specific inhibitors or siRNA-knockdown of PI3K, Akt, PKCδ, and NF-κB cascades. Taken together, our results indicated that HGF enhances migration of chondrosarcoma cells by increasing MMP-2 expression through the c-Met receptor/PI3K/Akt/PKCδ/NF-κB signal transduction pathway. PMID:23320110

HGF and c-Met interaction promotes migration in human chondrosarcoma cells.

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Hsi-Kai Tsou

Full Text Available Chondrosarcoma is a type of highly malignant tumor with a potent capacity for local invasion and causing distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Hepatocyte growth factor (HGF has been demonstrated to stimulate cancer proliferation, migration, and metastasis. However, the effect of HGF on migration activity of human chondrosarcoma cells is not well known. Here, we found that human chondrosarcoma tissues demonstrated significant expression of HGF, which was higher than that in normal cartilage. We also found that HGF increased the migration and expression of matrix metalloproteinase (MMP-2 in human chondrosarcoma cells. c-Met inhibitor and siRNA reduced HGF-increased cell migration and MMP-2 expression. HGF treatment resulted in activation of the phosphatidylinositol 3'-kinase (PI3K/Akt/PKCδ/NF-κB pathway, and HGF-induced expression of MMP-2 and cell migration was inhibited by specific inhibitors or siRNA-knockdown of PI3K, Akt, PKCδ, and NF-κB cascades. Taken together, our results indicated that HGF enhances migration of chondrosarcoma cells by increasing MMP-2 expression through the c-Met receptor/PI3K/Akt/PKCδ/NF-κB signal transduction pathway.

A possible role for the immune system in adult neurogenesis: new insights from an invertebrate model.

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Harzsch, Steffen; von Bohlen Und Halbach, Oliver

2016-04-01

Persistent neurogenesis in the adult brain of both vertebrates and invertebrates was previously considered to be driven by self-renewing neuronal stem cells of ectodermal origin. Recent findings in an invertebrate model challenge this view and instead provide evidence for a recruitment of neuronal precursors from a non-neuronal source. In the brain of adult crayfish, a neurogenic niche was identified that contributes progeny to the adult central olfactory pathway. The niche may function in attracting cells from the hemolymph and transforming them into cells with a neuronal fate. This finding implies that the first-generation neuronal precursors located in the crayfish neurogenic niche are not self-renewing. Evidence is summarized in support of a critical re-evaluation of long-term self-renewal of mammalian neuronal stem cells. Latest findings suggest that a tight link between the immune system and the system driving adult neurogenesis may not only exist in the crayfish but also in mammals. Copyright © 2015 Elsevier GmbH. All rights reserved.

Multiple modes of proepicardial cell migration require heartbeat.

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Plavicki, Jessica S; Hofsteen, Peter; Yue, Monica S; Lanham, Kevin A; Peterson, Richard E; Heideman, Warren

2014-05-15

The outermost layer of the vertebrate heart, the epicardium, forms from a cluster of progenitor cells termed the proepicardium (PE). PE cells migrate onto the myocardium to give rise to the epicardium. Impaired epicardial development has been associated with defects in valve development, cardiomyocyte proliferation and alignment, cardiac conduction system maturation and adult heart regeneration. Zebrafish are an excellent model for studying cardiac development and regeneration; however, little is known about how the zebrafish epicardium forms. We report that PE migration occurs through multiple mechanisms and that the zebrafish epicardium is composed of a heterogeneous population of cells. Heterogeneity is first observed within the PE and persists through epicardium formation. Using in vivo imaging, histology and confocal microscopy, we show that PE cells migrate through a cellular bridge that forms between the pericardial mesothelium and the heart. We also observed the formation of PE aggregates on the pericardial surface, which were released into the pericardial cavity. It was previously reported that heartbeat-induced pericardiac fluid advections are necessary for PE cluster formation and subsequent epicardium development. We manipulated heartbeat genetically and pharmacologically and found that PE clusters clearly form in the absence of heartbeat. However, when heartbeat was inhibited the PE failed to migrate to the myocardium and the epicardium did not form. We isolated and cultured hearts with only a few epicardial progenitor cells and found a complete epicardial layer formed. However, pharmacologically inhibiting contraction in culture prevented epicardium formation. Furthermore, we isolated control and silent heart (sih) morpholino (MO) injected hearts prior to epicardium formation (60 hpf) and co-cultured these hearts with "donor" hearts that had an epicardium forming (108 hpf). Epicardial cells from donor hearts migrated on to control but not sih MO

Cell migration or cytokinesis and proliferation? – Revisiting the “go or grow” hypothesis in cancer cells in vitro

International Nuclear Information System (INIS)

Garay, Tamás; Juhász, Éva; Molnár, Eszter; Eisenbauer, Maria; Czirók, András; Dekan, Barbara; László, Viktória; Hoda, Mir Alireza; Döme, Balázs; Tímár, József; Klepetko, Walter; Berger, Walter; Hegedűs, Balázs

2013-01-01

The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The “go or grow” hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on 35 cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive. - Highlights: • We investigated the “go or grow” hypothesis in human cancer cells in vitro. • Proliferation and migration positively correlate in melanoma and lung cancer cells. • Duration of cytokinesis and migration shows inverse correlation. • Increased FAK activation is present in highly motile melanoma cells

Mechano-sensing and cell migration: a 3D model approach

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Borau, C; García-Aznar, J M; Kamm, R D

2011-01-01

Cell migration is essential for tissue development in different physiological and pathological conditions. It is a complex process orchestrated by chemistry, biological factors, microstructure and surrounding mechanical properties. Focusing on the mechanical interactions, cells do not only exert forces on the matrix that surrounds them, but they also sense and react to mechanical cues in a process called mechano-sensing. Here, we hypothesize the involvement of mechano-sensing in the regulation of directional cell migration through a three-dimensional (3D) matrix. For this purpose, we develop a 3D numerical model of individual cell migration, which incorporates the mechano-sensing process of the cell as the main mechanism regulating its movement. Consistent with this hypothesis, we found that factors, such as substrate stiffness, boundary conditions and external forces, regulate specific and distinct cell movements

Cell intrinsic modulation of Wnt signaling controls neuroblast migration in C. elegans.

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Mentink, Remco A; Middelkoop, Teije C; Rella, Lorenzo; Ji, Ni; Tang, Chung Yin; Betist, Marco C; van Oudenaarden, Alexander; Korswagen, Hendrik C

2014-10-27

Members of the Wnt family of secreted signaling proteins are key regulators of cell migration and axon guidance. In the nematode C. elegans, the migration of the QR neuroblast descendants requires multiple Wnt ligands and receptors. We found that the migration of the QR descendants is divided into three sequential phases that are each mediated by a distinct Wnt signaling mechanism. Importantly, the transition from the first to the second phase, which is the main determinant of the final position of the QR descendants along the anteroposterior body axis, is mediated through a cell-autonomous process in which the time-dependent expression of a Wnt receptor turns on the canonical Wnt/β-catenin signaling response that is required to terminate long-range anterior migration. Our results show that, in addition to direct guidance of cell migration by Wnt morphogenic gradients, cell migration can also be controlled indirectly through cell-intrinsic modulation of Wnt signaling responses.

Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells.

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Demirci, Selami; Doğan, Ayşegül; Apdik, Hüseyin; Tuysuz, Emre Can; Gulluoglu, Sukru; Bayrak, Omer Faruk; Şahin, Fikrettin

2018-01-01

Cell proliferation and migration are crucial in many physiological processes including development, cancer, tissue repair, and wound healing. Cell migration is regulated by several signaling molecules. Identification of genes related to cell migration is required to understand molecular mechanism of non-healing chronic wounds which is a major concern in clinics. In the current study, the role of cytoglobin (CYGB) gene in fıbroblast cell migration and proliferation was described. L929 mouse fibroblast cells were transduced with lentiviral particles for CYGB and GFP, and analyzed for cell proliferation and migration ability. Fibroblast cells overexpressing CYGB displayed decreased cell proliferation, colony formation capacity, and cell migration. Phosphorylation levels of mTOR and two downstream effectors S6 and 4E-BP1 which take part in PI3K/AKT/mTOR signaling declined in CYGB-overexpressing cells. Microarray analysis indicated that CYGB overexpression leads to downregulation of cell proliferation, migration, and tumor growth associated genes in L929 cell line. This study demonstrated the role of CYGB in fibroblast cell motility and proliferation. CYGB could be a promising candidate for further studies as a potential target for diseases related to cell migration such as cancer and chronic wound treatment.

Effects of Maternal Behavior Induction and Pup Exposure on Neurogenesis in Adult, Virgin Female Rats

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Furuta, Miyako; Bridges, Robert S.

2009-01-01

The states of pregnancy and lactation bring about a range of physiological and behavioral changes in the adult mammal that prepare the mother to care for her young. Cell proliferation increases in the subventricular zone (SVZ) of the female rodent brain during both pregnancy and lactation when compared to that in cycling, diestrous females. In the present study, the effects of maternal behavior induction and pup exposure on neurogenesis in nulliparous rats were examined in order to determine whether maternal behavior itself, independent of pregnancy and lactation, might affect neurogenesis. Adult, nulliparous, Sprague-Dawley, female rats were exposed daily to foster young in order to induce maternal behavior. Following the induction of maternal behavior each maternal subject plus females that were exposed to pups for a comparable number of test days, but did not display maternal behavior, and subjects that had received no pup exposure were injected with bromodeoxyuridine (BrdU, 90 mg/kg, i.v.). Brain sections were double-labeled for BrdU and the neural marker, NeuN, to examine the proliferating cell population. Increases in the number of double-labeled cells were found in the maternal virgin brain when compared with the number of double-labeled cells present in non-maternal, pup-exposed nulliparous rats and in females not exposed to young. No changes were evident in the dentate gyrus of the hippocampus as a function of maternal behavior. These data indicate that in nulliparous female rats maternal behavior itself is associated with the stimulation of neurogenesis in the SVZ. PMID:19712726

The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells.

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Shao, Genbao; Wang, Ranran; Sun, Aiqin; Wei, Jing; Peng, Ke; Dai, Qian; Yang, Wannian; Lin, Qiong

2018-02-19

EGFR-dependent cell migration plays an important role in lung cancer progression. Our previous study observed that the HECT E3 ubiquitin ligase NEDD4 is significantly correlated with tumor metastasis and required for migration and invasion signaling of EGFR in gastric cancer cells. However, how NEDD4 promotes the EGFR-dependent lung cancer cell migration is unknown. This study is to elucidate the mechanism by which NEDD4 mediates the EGFR lung cancer migration signaling. Lentiviral vector-loaded NEDD4 shRNA was used to deplete endogenous NEDD4 in lung cancer cell lines. Effects of the NEDD4 knockdown on the EGFR-dependent or independent lung cancer cell migration were determined using the wound-healing and transwell assays. Association of NEDD4 with activated EGFR was assayed by co-immunoprecipitation. Co-expression of NEDD4 with EGFR or PTEN was determined by immunohistochemical (IHC) staining in 63 lung adenocarcinoma tissue samples. Effects of NEDD4 ectopic expression or knockdown on PTEN ubiquitination and down-regulation, AKT activation and lysosomal secretion were examined using the GST-Uba pulldown assay, immunoblotting, immunofluorescent staining and a human cathepsin B ELISA assay respectively. The specific cathepsin B inhibitor CA-074Me was used for assessing the role of cathepsin B in lung cancer cell migration. Knockdown of NEDD4 significantly reduced EGF-stimulated cell migration in non-small cell lung carcinoma (NSCLC) cells. Co-immunoprecipitation assay found that NEDD4 is associated with EGFR complex upon EGF stimulation, and IHC staining indicates that NEDD4 is co-expressed with EGFR in lung adenocarcinoma tumor tissues, suggesting that NEDD4 might mediate lung cancer cell migration by interaction with the EGFR signaling complex. Interestingly, NEDD4 promotes the EGF-induced cathepsin B secretion, possibly through lysosomal exocytosis, as overexpression of the ligase-dead mutant of NEDD4 impedes lysosomal secretion, and knockdown of NEDD4

Dentate Gyrus Neurogenesis, Integration, and microRNAs

OpenAIRE

Luikart, Bryan W; Perederiy, Julia V; Westbrook, Gary L

2011-01-01

Neurons are born and become a functional part of the synaptic circuitry in adult brains. The proliferative phase of neurogenesis has been extensively reviewed. We therefore focus this review on a few topics addressing the functional role of adult-generated newborn neurons in the dentate gyrus. We discuss the evidence for a link between neurogenesis and behavior. We then describe the steps in the integration of newborn neurons into a functioning mature synaptic circuit. Given the profound effe...

Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis

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Ning-Ning Song

2017-06-01

Full Text Available The central serotonin (5-HT system is the main target of selective serotonin reuptake inhibitors (SSRIs, the first-line antidepressants widely used in current general practice. One of the prominent features of chronic SSRI treatment in rodents is the enhanced adult neurogenesis in the hippocampus, which has been proposed to contribute to antidepressant effects. Therefore, tremendous effort has been made to decipher how central 5-HT regulates adult hippocampal neurogenesis. In this paper, we review how changes in the central serotonergic system alter adult hippocampal neurogenesis. We focus on data obtained from three categories of genetically engineered mouse models: (1 mice with altered central 5-HT levels from embryonic stages, (2 mice with deletion of 5-HT receptors from embryonic stages, and (3 mice with altered central 5-HT system exclusively in adulthood. These recent findings provide unique insights to interpret the multifaceted roles of central 5-HT on adult hippocampal neurogenesis and its associated effects on depression.

Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells

International Nuclear Information System (INIS)

Brusevold, Ingvild J; Tveteraas, Ingun H; Aasrum, Monica; Ødegård, John; Sandnes, Dagny L; Christoffersen, Thoralf

2014-01-01

Oral squamous cell carcinoma is an aggressive neoplasm with serious morbidity and mortality, which typically spreads through local invasive growth. Lysophosphatidic acid (LPA) is involved in a number of biological processes, and may have a role in cancer cell migration and invasiveness. LPA is present in most tissues and can activate cells through six different LPA receptors (LPAR1-6). Although LPA is predominantly promigratory, some of the receptors may have antimigratory effects in certain cells. The signalling mechanisms of LPA are not fully understood, and in oral carcinoma cells the specific receptors and pathways involved in LPA-stimulated migration are unknown. The oral carcinoma cell lines E10, SCC-9, and D2 were investigated. Cell migration was studied in a scratch wound assay, and invasion was demonstrated in organotypic three dimensional co-cultures. Protein and mRNA expression of LPA receptors was studied with Western blotting and qRT-PCR. Activation of signalling proteins was examined with Western blotting and isoelectric focusing, and signalling mechanisms were further explored using pharmacological agents and siRNA directed at specific receptors and pathways. LPA stimulated cell migration in the two oral carcinoma cell lines E10 and SCC-9, but was slightly inhibitory in D2. The receptor expression profile and the effects of specific pharmacological antagonist and agonists indicated that LPA-stimulated cell migration was mediated through LPAR3 in E10 and SCC-9. Furthermore, in both these cell lines, the stimulation by LPA was dependent on PKC activity. However, while LPA induced transactivation of EGFR and the stimulated migration was blocked by EGFR inhibitors in E10 cells, LPA did not induce EGFR transactivation in SCC-9 cells. In D2 cells, LPA induced EGFR transactivation, but this was associated with slowing of a very high inherent migration rate in these cells. The results demonstrate LPA-stimulated migration in oral carcinoma cells through LPAR3

The effects of acoustic vibration on fibroblast cell migration.

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Mohammed, Taybia; Murphy, Mark F; Lilley, Francis; Burton, David R; Bezombes, Frederic

2016-12-01

Cells are known to interact and respond to external mechanical cues and recent work has shown that application of mechanical stimulation, delivered via acoustic vibration, can be used to control complex cell behaviours. Fibroblast cells are known to respond to physical cues generated in the extracellular matrix and it is thought that such cues are important regulators of the wound healing process. Many conditions are associated with poor wound healing, so there is need for treatments/interventions, which can help accelerate the wound healing process. The primary aim of this research was to investigate the effects of mechanical stimulation upon the migratory and morphological properties of two different fibroblast cells namely; human lung fibroblast cells (LL24) and subcutaneous areolar/adipose mouse fibroblast cells (L929). Using a speaker-based system, the effects of mechanical stimulation (0-1600Hz for 5min) on the mean cell migration distance (μm) and actin organisation was investigated. The results show that 100Hz acoustic vibration enhanced cell migration for both cell lines whereas acoustic vibration above 100Hz was found to decrease cell migration in a frequency dependent manner. Mechanical stimulation was also found to promote changes to the morphology of both cell lines, particularly the formation of lamellipodia and filopodia. Overall lamellipodia was the most prominent actin structure displayed by the lung cell (LL24), whereas filopodia was the most prominent actin feature displayed by the fibroblast derived from subcutaneous areolar/adipose tissue. Mechanical stimulation at all the frequencies used here was found not to affect cell viability. These results suggest that low-frequency acoustic vibration may be used as a tool to manipulate the mechanosensitivity of cells to promote cell migration. Copyright © 2016 Elsevier B.V. All rights reserved.

p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex

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Camille Belzil

2014-05-01

Full Text Available Apical neural progenitors (aNPs drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600 in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.

CD155/PVR plays a key role in cell motility during tumor cell invasion and migration

International Nuclear Information System (INIS)

Sloan, Kevin E; Ilag, Leodevico L; Jay, Daniel G; Eustace, Brenda K; Stewart, Jean K; Zehetmeier, Carol; Torella, Claudia; Simeone, Marina; Roy, Jennifer E; Unger, Christine; Louis, David N

2004-01-01

Invasion is an important early step of cancer metastasis that is not well understood. Developing therapeutics to limit metastasis requires the identification and validation of candidate proteins necessary for invasion and migration. We developed a functional proteomic screen to identify mediators of tumor cell invasion. This screen couples Fluorophore Assisted Light Inactivation (FALI) to a scFv antibody library to systematically inactivate surface proteins expressed by human fibrosarcoma cells followed by a high-throughput assessment of transwell invasion. Using this screen, we have identified CD155 (the poliovirus receptor) as a mediator of tumor cell invasion through its role in migration. Knockdown of CD155 by FALI or by RNAi resulted in a significant decrease in transwell migration of HT1080 fibrosarcoma cells towards a serum chemoattractant. CD155 was found to be highly expressed in multiple cancer cell lines and primary tumors including glioblastoma (GBM). Knockdown of CD155 also decreased migration of U87MG GBM cells. CD155 is recruited to the leading edge of migrating cells where it colocalizes with actin and αv-integrin, known mediators of motility and adhesion. Knockdown of CD155 also altered cellular morphology, resulting in cells that were larger and more elongated than controls when plated on a Matrigel substrate. These results implicate a role for CD155 in mediating tumor cell invasion and migration and suggest that CD155 may contribute to tumorigenesis

Aquaporin 2 promotes cell migration and epithelial morphogenesis.

Science.gov (United States)

Chen, Ying; Rice, William; Gu, Zhizhan; Li, Jian; Huang, Jianmin; Brenner, Michael B; Van Hoek, Alfred; Xiong, Jianping; Gundersen, Gregg G; Norman, Jim C; Hsu, Victor W; Fenton, Robert A; Brown, Dennis; Lu, Hua A Jenny

2012-09-01

The aquaporin 2 (AQP2) water channel, expressed in kidney collecting ducts, contributes critically to water homeostasis in mammals. Animals lacking or having significantly reduced levels of AQP2, however, have not only urinary concentrating abnormalities but also renal tubular defects that lead to neonatal mortality from renal failure. Here, we show that AQP2 is not only a water channel but also an integrin-binding membrane protein that promotes cell migration and epithelial morphogenesis. AQP2 expression modulates the trafficking and internalization of integrin β1, facilitating its turnover at focal adhesions. In vitro, disturbing the interaction between AQP2 and integrin β1 by mutating the RGD motif led to reduced endocytosis, retention of integrin β1 at the cell surface, and defective cell migration and tubulogenesis. Similarly, in vivo, AQP2-null mice exhibited significant retention of integrin β1 at the basolateral membrane and had tubular abnormalities. In summary, these data suggest that the water channel AQP2 interacts with integrins to promote renal epithelial cell migration, contributing to the structural and functional integrity of the mammalian kidney.

Effects of rapamycin treatment after controlled cortical impact injury on neurogenesis and synaptic reorganization in the mouse dentate gyrus

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Corwin R Butler

2015-11-01

Full Text Available Post-traumatic epilepsy (PTE is one consequence of traumatic brain injury (TBI. A prominent cell signaling pathway activated in animal models of both TBI and epilepsy is the mammalian target of rapamycin (mTOR. Inhibition of mTOR with rapamycin has shown promise as a potential modulator of epileptogenesis in several animal models of epilepsy, but cellular mechanisms linking mTOR expression and epileptogenesis are unclear. In this study, the role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI induced by controlled cortical impact was investigated. Rapamycin (3 or 10 mg/kg, an inhibitor of mTOR signaling, was administered by intraperitoneal injection beginning on the day of injury and continued daily until tissue collection. Relative to controls, rapamycin treatment reduced dentate granule cell area in the hemisphere ipsilateral to the injury two weeks post-injury. Brain injury resulted in a significant increase in doublecortin immunolabeling in the dentate gyrus ipsilateral to the injury, indicating increased neurogenesis shortly after TBI. Rapamycin treatment prevented the increase in doublecortin labeling, with no overall effect on Fluoro-Jade B staining in the ipsilateral hemisphere, suggesting that rapamycin treatment reduced posttraumatic neurogenesis but did not prevent cell loss after injury. At later times post-injury (8-13 weeks, evidence of mossy fiber sprouting and increased recurrent excitation of dentate granule cells was detected, which were attenuated by rapamycin treatment. Rapamycin treatment also diminished seizure prevalence relative to vehicle-treated controls after TBI. Collectively, these results support a role for adult neurogenesis in PTE development and suggest that suppression of epileptogenesis by mTOR inhibition includes effects on post-injury neurogenesis.

Microfabricated physical spatial gradients for investigating cell migration and invasion dynamics.

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Michael Mak

Full Text Available We devise a novel assay that introduces micro-architectures into highly confining microchannels to probe the decision making processes of migrating cells. The conditions are meant to mimic the tight spaces in the physiological environment that cancer cells encounter during metastasis within the matrix dense stroma and during intravasation and extravasation through the vascular wall. In this study we use the assay to investigate the relative probabilities of a cell 1 permeating and 2 repolarizing (turning around when it migrates into a spatially confining region. We observe the existence of both states even within a single cell line, indicating phenotypic heterogeneity in cell migration invasiveness and persistence. We also show that varying the spatial gradient of the taper can induce behavioral changes in cells, and different cell types respond differently to spatial changes. Particularly, for bovine aortic endothelial cells (BAECs, higher spatial gradients induce more cells to permeate (60% than lower gradients (12%. Furthermore, highly metastatic breast cancer cells (MDA-MB-231 demonstrate a more invasive and permeative nature (87% than non-metastatic breast epithelial cells (MCF-10A (25%. We examine the migration dynamics of cells in the tapered region and derive characteristic constants that quantify this transition process. Our data indicate that cell response to physical spatial gradients is both cell-type specific and heterogeneous within a cell population, analogous to the behaviors reported to occur during tumor progression. Incorporation of micro-architectures in confined channels enables the probing of migration behaviors specific to defined geometries that mimic in vivo microenvironments.

Juvenile neurogenesis makes essential contributions to adult brain structure and plays a sex-dependent role in fear memories

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Jesse Daniel Cushman

2012-02-01

Full Text Available Postnatal-neurogenesis (PNN contributes neurons to olfactory bulb (OB and dentate gyrus (DG throughout juvenile development, but the quantitative amount, temporal dynamics and functional roles of this contribution have not been defined. By using transgenic mouse models for cell lineage tracing and conditional cell ablation, we found that juvenile neurogenesis gradually increased the total number of granule neurons by approximately 40% in OB, and by 25% in DG, between two weeks and two months of age, and that total numbers remained stable thereafter. These findings indicate that the overwhelming majority of net postnatal neuronal addition in these regions occurs during the juvenile period and that adult neurogenesis contributes primarily to replacement of granule cells in both regions. Behavioral analysis in our conditional cell ablation mouse model showed that complete loss of PNN throughout both the juvenile and adult period produced a specific set of sex-dependent cognitive changes. We observed normal hippocampus-independent delay fear conditioning, but excessive generalization of fear to a novel auditory stimulus, which is consistent with a role for PNN in psychopathology. Standard contextual fear conditioning was intact, however, pre-exposure dependent contextual fear was impaired suggesting a specific role for PNN in incidental contextual learning. Contextual discrimination between two highly similar contexts was enhanced; suggesting either enhanced contextual pattern separation or impaired temporal integration. We also observed a reduced reliance on olfactory cues, consistent with a role for OB PNN in the efficient processing of olfactory information. Thus, juvenile neurogenesis adds substantively to the total numbers of granule neurons in OB and DG during periods of critical juvenile behavioral development, including weaning, early social interactions and sexual maturation, and plays a sex-dependent role in fear memories.

Epithelial-mesenchymal transition transcription factors control pluripotent adult stem cell migration in vivo in planarians

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Abnave, Prasad; Aboukhatwa, Ellen; Kosaka, Nobuyoshi; Thompson, James; Hill, Mark A.

2017-01-01

Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infection. Inappropriate migration also underpins metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in planarians. We demonstrate the use of this system to study the molecular control of stem cell migration and show that snail-1, snail-2 and zeb-1 EMT transcription factor homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. We also observed that stem cells undergo homeostatic migration to anterior regions that lack local stem cells, in the absence of injury, maintaining tissue homeostasis. This requires the polarity determinant notum. Our work establishes planarians as a suitable model for further in-depth study of the processes controlling stem cell migration in vivo. PMID:28893948

Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin

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Ryan P. Vetreno

2018-03-01

Full Text Available Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55, we tested the hypothesis that AIE-induced upregulation of neuroimmune signaling contributes to the loss of hippocampal neurogenesis in adulthood. We found that AIE caused upregulation of multiple proinflammatory Toll-like receptors (TLRs, increased expression of phosphorylated NF-κB p65 (pNF-κB p65 and the cell death marker cleaved caspase 3, and reduced markers of neurogenesis in the adult (P80 hippocampus, which is consistent with persistently increased neuroimmune signaling reducing neurogenesis. We observed a similar increase of pNF-κB p65-immunoreactive cells in the post-mortem human alcoholic hippocampus, an effect that was negatively correlated with age of drinking onset. Voluntary wheel running from P24 to P80 prevented the AIE-induced loss of neurogenesis markers (i.e., nestin and doublecortin in the adult hippocampus that was paralleled by blockade of increased expression of the cell death marker cleaved caspase 3. Wheel running also prevented the AIE-induced increase of hippocampal pNF-κB p65 and induction of neuroimmune NF-κB target genes, including TNFα and IκBα in the adult brain. Administration of the anti-inflammatory drug indomethacin during AIE prevented the loss of neurogenesis markers (i.e., nestin and doublecortin and the concomitant increase of cleaved caspase 3, an effect that was accompanied by blockade of the increase of pNF-κB p65. Similarly, administration of the proinflammatory TLR4 activator lipopolysaccharide resulted in a loss of doublecortin that was paralleled by increased

Sensing of substratum rigidity and directional migration by fast-crawling cells

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Okimura, Chika; Sakumura, Yuichi; Shimabukuro, Katsuya; Iwadate, Yoshiaki

2018-05-01

Living cells sense the mechanical properties of their surrounding environment and respond accordingly. Crawling cells detect the rigidity of their substratum and migrate in certain directions. They can be classified into two categories: slow-moving and fast-moving cell types. Slow-moving cell types, such as fibroblasts, smooth muscle cells, mesenchymal stem cells, etc., move toward rigid areas on the substratum in response to a rigidity gradient. However, there is not much information on rigidity sensing in fast-moving cell types whose size is ˜10 μ m and migration velocity is ˜10 μ m /min . In this study, we used both isotropic substrata with different rigidities and an anisotropic substratum that is rigid on the x axis but soft on the y axis to demonstrate rigidity sensing by fast-moving Dictyostelium cells and neutrophil-like differentiated HL-60 cells. Dictyostelium cells exerted larger traction forces on a more rigid isotropic substratum. Dictyostelium cells and HL-60 cells migrated in the "soft" direction on the anisotropic substratum, although myosin II-null Dictyostelium cells migrated in random directions, indicating that rigidity sensing of fast-moving cell types differs from that of slow types and is induced by a myosin II-related process.

Computational models reveal a passive mechanism for cell migration in the crypt.

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Sara-Jane Dunn

Full Text Available Cell migration in the intestinal crypt is essential for the regular renewal of the epithelium, and the continued upward movement of cells is a key characteristic of healthy crypt dynamics. However, the driving force behind this migration is unknown. Possibilities include mitotic pressure, active movement driven by motility cues, or negative pressure arising from cell loss at the crypt collar. It is possible that a combination of factors together coordinate migration. Here, three different computational models are used to provide insight into the mechanisms that underpin cell movement in the crypt, by examining the consequence of eliminating cell division on cell movement. Computational simulations agree with existing experimental results, confirming that migration can continue in the absence of mitosis. Importantly, however, simulations allow us to infer mechanisms that are sufficient to generate cell movement, which is not possible through experimental observation alone. The results produced by the three models agree and suggest that cell loss due to apoptosis and extrusion at the crypt collar relieves cell compression below, allowing cells to expand and move upwards. This finding suggests that future experiments should focus on the role of apoptosis and cell extrusion in controlling cell migration in the crypt.

Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration.

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Sylvie Lachmann

Full Text Available The mammalian protein kinase N (PKN family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration.

Science.gov (United States)

Lachmann, Sylvie; Jevons, Amy; De Rycker, Manu; Casamassima, Adele; Radtke, Simone; Collazos, Alejandra; Parker, Peter J

2011-01-01

The mammalian protein kinase N (PKN) family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s) of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

Role of laminin receptor in tumor cell migration

DEFF Research Database (Denmark)

Wewer, U M; Taraboletti, G; Sobel, M E

1987-01-01

Polyclonal antisera were made against biochemically purified laminin receptor protein as well as against synthetic peptides deduced from a complementary DNA clone corresponding to the COOH-terminal end of the laminin receptor (U.M. Wewer et al., Proc. Natl. Acad. Sci. USA, 83: 7137-7141, 1986......). These antisera were used to study the potential role of laminin receptor in laminin-mediated attachment and haptotactic migration of human A2058 melanoma cells. The anti-laminin receptor antisera reacted with the surface of suspended, nonpermeabilized melanoma and carcinoma cells. The anti-laminin receptor...... antisera blocked the surface interaction of A2058 cells with endogenous laminin, resulting in the inhibition of laminin-mediated cell attachment. The A2058 melanoma cells migrated toward a gradient of solid phase laminin or fibronectin (haptotaxis). Anti-laminin antiserum abolished haptotaxis on laminin...

Analysis of primary cilia in directional cell migration in fibroblasts

DEFF Research Database (Denmark)

Christensen, Søren Tvorup; Veland, Iben; Schwab, Albrecht

2013-01-01

summarize selected methods in analyzing ciliary function in directional cell migration, including immunofluorescence microscopy, scratch assay, and chemotaxis assay by micropipette addition of PDGFRα ligands to cultures of fibroblasts. These methods should be useful not only in studying cell migration....... In particular, platelet-derived growth factor receptor alpha (PDGFRα) is compartmentalized to the primary cilium to activate signaling pathways that regulate reorganization of the cytoskeleton required for lamellipodium formation and directional migration in the presence of a specific ligand gradient. We...

Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration