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Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem...
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Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 32717

Special Issue Editors

Dr. Florian Siebzehnrubl

E-Mail Website
Guest Editor
Cardiff University, Cardiff, UK
Interests: adult neural stem cells; astrocytes; brain cancer; stem cell transcription factors
Dr. David Petrik

E-Mail Website
Guest Editor
Cardiff University, Cardiff, UK
Interests: adult neural stem cells; adult neurogenesis; newborn neurons; hippocampus; hypothalamus

Special Issue Information

Dear Colleagues,

Neurogenesis in the adult mammalian brain has been implicated in learning and memory and mood control. During the past three decades, the process of adult neurogenesis has been determined in the hippocampus and the walls of lateral ventricles. The molecular and cellular determinants and stages of the process have been mapped in extensive detail. However, recent discoveries in the field challenge certain aspects of adult neurogenesis.

This Special Issue will address the nature and clonality of adult neural stem cells, the extent of adult neurogenesis in non-canonical regions and in the human brain, non-invasive detection and single-cell analysis of neural stem cells in the brain, and regulation of neurogenesis by intrinsic and extrinsic factors.

Dr. Florian Siebzehnrubl
Dr. David Petrik
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurogenesis
  • neural stem cells
  • regulation, function and detection of adult neurogenesis
  • extent of adult neurogenesis

Published Papers (11 papers)

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Research

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24 pages, 3960 KiB  
Article
Post-Stroke Environmental Enrichment Improves Neurogenesis and Cognitive Function and Reduces the Generation of Aberrant Neurons in the Mouse Hippocampus
by Florus Woitke, Antonia Blank, Anna-Lena Fleischer, Shanshan Zhang, Gina-Marie Lehmann, Julius Broesske, Madlen Haase, Christoph Redecker, Christian W. Schmeer and Silke Keiner
Cells 2023, 12(4), 652; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12040652 - 17 Feb 2023
Cited by 9 | Viewed by 1653
Abstract
Ischemic lesions stimulate adult neurogenesis in the dentate gyrus, however, this is not associated with better cognitive function. Furthermore, increased neurogenesis is associated with the formation of aberrant neurons. In a previous study, we showed that a running task after a stroke not [...] Read more.
Ischemic lesions stimulate adult neurogenesis in the dentate gyrus, however, this is not associated with better cognitive function. Furthermore, increased neurogenesis is associated with the formation of aberrant neurons. In a previous study, we showed that a running task after a stroke not only increases neurogenesis but also the number of aberrant neurons without improving general performance. Here, we determined whether stimulation in an enriched environment after a lesion could increase neurogenesis and cognitive function without enhancing the number of aberrant neurons. After an ischemic stroke induced by MCAO, animals were transferred to an enriched environment containing a running wheel, tunnels and nest materials. A GFP-retroviral vector was delivered on day 3 post-stroke and a modified water maze test was performed 6 weeks after the lesion. We found that the enriched environment significantly increased the number of new neurons compared with the unstimulated stroke group but not the number of aberrant cells after a lesion. Increased neurogenesis after environmental enrichment was associated with improved cognitive function. Our study showed that early placement in an enriched environment after a stroke lesion markedly increased neurogenesis and flexible learning but not the formation of aberrant neurons, indicating that rehabilitative training, as a combination of running wheel training and enriched environment housing, improved functional and structural outcomes after a stroke. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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15 pages, 2360 KiB  
Article
Synthetic Thymidine Analog Labeling without Misconceptions
by Anna Ivanova, Olesya Gruzova, Elizaveta Ermolaeva, Olga Astakhova, Sheed Itaman, Grigori Enikolopov and Alexander Lazutkin
Cells 2022, 11(12), 1888; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11121888 - 10 Jun 2022
Cited by 4 | Viewed by 2368
Abstract
Tagging proliferating cells with thymidine analogs is an indispensable research tool; however, the issue of the potential in vivo cytotoxicity of these compounds remains unresolved. Here, we address these concerns by examining the effects of BrdU and EdU on adult hippocampal neurogenesis and [...] Read more.
Tagging proliferating cells with thymidine analogs is an indispensable research tool; however, the issue of the potential in vivo cytotoxicity of these compounds remains unresolved. Here, we address these concerns by examining the effects of BrdU and EdU on adult hippocampal neurogenesis and EdU on the perinatal somatic development of mice. We show that, in a wide range of doses, EdU and BrdU label similar numbers of cells in the dentate gyrus shortly after administration. Furthermore, whereas the administration of EdU does not affect the division and survival of neural progenitor within 48 h after injection, it does affect cell survival, as evaluated 6 weeks later. We also show that a single injection of various doses of EdU on the first postnatal day does not lead to noticeable changes in a panel of morphometric criteria within the first week; however, higher doses of EdU adversely affect the subsequent somatic maturation and brain growth of the mouse pups. Our results indicate the potential caveats in labeling the replicating DNA using thymidine analogs and suggest guidelines for applying this approach. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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17 pages, 2922 KiB  
Article
Divergence between Neuronal and Oligodendroglial Cell Fate, in Postnatal Brain Neural Stem Cells, Leads to Divergent Properties in Polymorphic In Vitro Assays
by Maria Anesti, Stavroula Magkafa, Efstathia Prantikou and Ilias Kazanis
Cells 2022, 11(11), 1743; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11111743 - 25 May 2022
Cited by 1 | Viewed by 1984
Abstract
Two main stem cell pools exist in the postnatal mammalian brain that, although they share some “stemness” properties, also exhibit significant differences. Multipotent neural stem cells survive within specialized microenvironments, called niches, and they are vulnerable to ageing. Oligodendroglial lineage-restricted progenitor cells are [...] Read more.
Two main stem cell pools exist in the postnatal mammalian brain that, although they share some “stemness” properties, also exhibit significant differences. Multipotent neural stem cells survive within specialized microenvironments, called niches, and they are vulnerable to ageing. Oligodendroglial lineage-restricted progenitor cells are widely distributed in the brain parenchyma and are more resistant to the effects of ageing. Here, we create polymorphic neural stem cell cultures and allow cells to progress towards the neuronal and the oligodendroglial lineage. We show that the divergence of cell fate is accompanied by a divergence in the properties of progenitors, which reflects their adaptation to life in the niche or the parenchyma. Neurogenesis shows significant spatial restrictions and a dependence on laminin, a major niche component, while oligodendrogenesis shows none of these constraints. Furthermore, the blocking of integrin-β1 leads to opposing effects, reducing neurogenesis and enhancing oligodendrogenesis. Therefore, polymorphic neural stem cell assays can be used to investigate the divergence of postnatal brain stem cells and also to predict the in vivo effects of potential therapeutic molecules targeting stem and progenitor cells, as we do for the microneurotrophin BNN-20. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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20 pages, 8796 KiB  
Article
Impaired Generation of Transit-Amplifying Progenitors in the Adult Subventricular Zone of Cyclin D2 Knockout Mice
by Rafał Płatek, Piotr Rogujski, Jarosław Mazuryk, Marta B. Wiśniewska, Leszek Kaczmarek and Artur Czupryn
Cells 2022, 11(1), 135; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010135 - 01 Jan 2022
Cited by 5 | Viewed by 2999
Abstract
In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the [...] Read more.
In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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14 pages, 1458 KiB  
Article
Electroconvulsive Shock, but Not Transcranial Magnetic Stimulation, Transiently Elevates Cell Proliferation in the Adult Mouse Hippocampus
by Tian Rui Zhang, Evelyn Guilherme, Aydan Kesici, Alyssa M. Ash, Fidel Vila-Rodriguez and Jason S. Snyder
Cells 2021, 10(8), 2090; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082090 - 14 Aug 2021
Cited by 4 | Viewed by 3007
Abstract
Hippocampal plasticity is hypothesized to play a role in the etiopathogenesis of depression and the antidepressant effect of medications. One form of plasticity that is unique to the hippocampus and is involved in depression-related behaviors in animal models is adult neurogenesis. While chronic [...] Read more.
Hippocampal plasticity is hypothesized to play a role in the etiopathogenesis of depression and the antidepressant effect of medications. One form of plasticity that is unique to the hippocampus and is involved in depression-related behaviors in animal models is adult neurogenesis. While chronic electroconvulsive shock (ECS) strongly promotes neurogenesis, less is known about its acute effects and little is known about the neurogenic effects of other forms of stimulation therapy, such as repetitive transcranial magnetic stimulation (rTMS). Here, we investigated the time course of acute ECS and rTMS effects on markers of cell proliferation and neurogenesis in the adult hippocampus. Mice were subjected to a single session of ECS, 10 Hz rTMS (10–rTMS), or intermittent theta burst stimulation (iTBS). Mice in both TMS groups were injected with BrdU 2 days before stimulation to label immature cells. One, 3, or 7 days later, hippocampi were collected and immunostained for BrdU + cells, actively proliferating PCNA + cells, and immature DCX + neurons. Following ECS, mice displayed a transient increase in cell proliferation at 3 days post-stimulation. At 7 days post–stimulation there was an elevation in the number of proliferating neuronal precursor cells (PCNA + DCX +), specifically in the ventral hippocampus. iTBS and rTMS did not alter the number of BrdU + cells, proliferating cells, or immature neurons at any of the post-stimulation time points. Our results suggest that neurostimulation treatments exert different effects on hippocampal neurogenesis, where ECS may have greater neurogenic potential than iTBS and 10–rTMS. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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Review

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19 pages, 2010 KiB  
Review
Endogenous Neural Stem Cell Mediated Oligodendrogenesis in the Adult Mammalian Brain
by Daniel Z. Radecki and Jayshree Samanta
Cells 2022, 11(13), 2101; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132101 - 02 Jul 2022
Cited by 3 | Viewed by 3500
Abstract
Oligodendrogenesis is essential for replacing worn-out oligodendrocytes, promoting myelin plasticity, and for myelin repair following a demyelinating injury in the adult mammalian brain. Neural stem cells are an important source of oligodendrocytes in the adult brain; however, there are considerable differences in oligodendrogenesis [...] Read more.
Oligodendrogenesis is essential for replacing worn-out oligodendrocytes, promoting myelin plasticity, and for myelin repair following a demyelinating injury in the adult mammalian brain. Neural stem cells are an important source of oligodendrocytes in the adult brain; however, there are considerable differences in oligodendrogenesis from neural stem cells residing in different areas of the adult brain. Amongst the distinct niches containing neural stem cells, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are considered the principle areas of adult neurogenesis. In addition to these areas, radial glia-like cells, which are the precursors of neural stem cells, are found in the lining of the third ventricle, where they are called tanycytes, and in the cerebellum, where they are called Bergmann glia. In this review, we will describe the contribution and regulation of each of these niches in adult oligodendrogenesis. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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21 pages, 1361 KiB  
Review
A Nuclear Belt Fastens on Neural Cell Fate
by Ivan Mestres, Judith Houtman, Federico Calegari and Tomohisa Toda
Cells 2022, 11(11), 1761; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11111761 - 27 May 2022
Cited by 4 | Viewed by 2718
Abstract
Successful embryonic and adult neurogenesis require proliferating neural stem and progenitor cells that are intrinsically and extrinsically guided into a neuronal fate. In turn, migration of new-born neurons underlies the complex cytoarchitecture of the brain. Proliferation and migration are therefore essential for brain [...] Read more.
Successful embryonic and adult neurogenesis require proliferating neural stem and progenitor cells that are intrinsically and extrinsically guided into a neuronal fate. In turn, migration of new-born neurons underlies the complex cytoarchitecture of the brain. Proliferation and migration are therefore essential for brain development, homeostasis and function in adulthood. Among several tightly regulated processes involved in brain formation and function, recent evidence points to the nuclear envelope (NE) and NE-associated components as critical new contributors. Classically, the NE was thought to merely represent a barrier mediating selective exchange between the cytoplasm and nucleoplasm. However, research over the past two decades has highlighted more sophisticated and diverse roles for NE components in progenitor fate choice and migration of their progeny by tuning gene expression via interactions with chromatin, transcription factors and epigenetic factors. Defects in NE components lead to neurodevelopmental impairments, whereas age-related changes in NE components are proposed to influence neurodegenerative diseases. Thus, understanding the roles of NE components in brain development, maintenance and aging is likely to reveal new pathophysiological mechanisms for intervention. Here, we review recent findings for the previously underrepresented contribution of the NE in neuronal commitment and migration, and envision future avenues for investigation. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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18 pages, 327 KiB  
Review
Single-Cell and Single-Nucleus RNAseq Analysis of Adult Neurogenesis
by Alena Kalinina and Diane Lagace
Cells 2022, 11(10), 1633; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101633 - 13 May 2022
Cited by 7 | Viewed by 4155
Abstract
The complexity of adult neurogenesis is becoming increasingly apparent as we learn more about cellular heterogeneity and diversity of the neurogenic lineages and stem cell niches within the adult brain. This complexity has been unraveled in part due to single-cell and single-nucleus RNA [...] Read more.
The complexity of adult neurogenesis is becoming increasingly apparent as we learn more about cellular heterogeneity and diversity of the neurogenic lineages and stem cell niches within the adult brain. This complexity has been unraveled in part due to single-cell and single-nucleus RNA sequencing (sc-RNAseq and sn-RNAseq) studies that have focused on adult neurogenesis. This review summarizes 33 published studies in the field of adult neurogenesis that have used sc- or sn-RNAseq methods to answer questions about the three main regions that host adult neural stem cells (NSCs): the subventricular zone (SVZ), the dentate gyrus (DG) of the hippocampus, and the hypothalamus. The review explores the similarities and differences in methodology between these studies and provides an overview of how these studies have advanced the field and expanded possibilities for the future. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
10 pages, 301 KiB  
Review
Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis
by Martina Sassi, Alwena H. Morgan and Jeffrey S. Davies
Cells 2022, 11(5), 765; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050765 - 22 Feb 2022
Cited by 4 | Viewed by 2420
Abstract
Adult hippocampal neurogenesis—the generation of new functional neurones in the adult brain—is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits [...] Read more.
Adult hippocampal neurogenesis—the generation of new functional neurones in the adult brain—is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits it, thus demonstrating a previously unknown function of unacyl-ghrelin in modulating hippocampal plasticity. Analysis of plasma samples from Parkinson’s disease patients with dementia demonstrated a reduced acyl-ghrelin:unacyl-ghrelin ratio compared to both healthy controls and cognitively intact Parkinson’s disease patients. These data, from mouse and human studies, suggest that restoring acyl-ghrelin signalling may promote the activation of pathways to support memory function. In this short review, we discuss the evidence for ghrelin’s role in regulating adult hippocampal neurogenesis and the enzymes involved in ghrelin acylation and de-acylation as targets to treat mood-related disorders and dementia. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
22 pages, 856 KiB  
Review
Singular Adult Neural Stem Cells Do Not Exist
by David Petrik, Sara Jörgensen, Vasileios Eftychidis and Florian A. Siebzehnrubl
Cells 2022, 11(4), 722; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040722 - 18 Feb 2022
Cited by 5 | Viewed by 3983
Abstract
Adult neural stem cells (aNSCs) are the source for the continuous production of new neurons throughout life. This so-called adult neurogenesis has been extensively studied; the intermediate cellular stages are well documented. Recent discoveries have raised new controversies in the field, such as [...] Read more.
Adult neural stem cells (aNSCs) are the source for the continuous production of new neurons throughout life. This so-called adult neurogenesis has been extensively studied; the intermediate cellular stages are well documented. Recent discoveries have raised new controversies in the field, such as the notion that progenitor cells hold similar self-renewal potential as stem cells, or whether different types of aNSCs exist. Here, we discuss evidence for heterogeneity of aNSCs, including short-term and long-term self-renewing aNSCs, regional and temporal differences in aNSC function, and single cell transcriptomics. Reviewing various genetic mouse models used for targeting aNSCs and lineage tracing, we consider potential lineage relationships between Ascl1-, Gli1-, and Nestin-targeted aNSCs. We present a multidimensional model of adult neurogenesis that incorporates recent findings and conclude that stemness is a phenotype, a state of properties that can change with time, rather than a cell property, which is static and immutable. We argue that singular aNSCs do not exist. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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Other

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9 pages, 1004 KiB  
Brief Report
Enduring Effects of Conditional Brain Serotonin Knockdown, Followed by Recovery, on Adult Rat Neurogenesis and Behavior
by Maria Sidorova, Golo Kronenberg, Susann Matthes, Markus Petermann, Rainer Hellweg, Oksana Tuchina, Michael Bader, Natalia Alenina and Friederike Klempin
Cells 2021, 10(11), 3240; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113240 - 19 Nov 2021
Cited by 2 | Viewed by 2186
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. [...] Read more.
Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism. Full article
(This article belongs to the Special Issue Concepts and Controversies in Adult Neurogenesis and Adult Neural Stem Cells)
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