• aging
• differentiation
• hematopoietic stem cells
• heterogeneity
• muscle stem cells
• neural stem cells
• quiescence
• stem cells

• cell models
• neural stem cells
• neurodegenerative disorders
• neurogenesis
• pluripotent stem cells
• stem-cell-based therapy

• Humans
• Neurodegenerative Diseases/pathology
• Neurodegenerative Diseases/therapy
• Aging/pathology
• Stem Cells/metabolism
• Animals

• Milk fat globule epidermal growth factor 8
• apoptosis
• immunomodulatory
• inflammation
• neurodegenerative diseases

• astrocyte reactivity
• astrocytes
• clonal analysis
• lesion induced neurogenesis
• neural stem cells
• neurogenic potential
• parenchymal neurogenesis
• spatial statistics
• stem cell dynamics
• stem cell quiescence

• Animals
• Astrocytes/metabolism
• Astrocytes/cytology
• Neurogenesis
• Neural Stem Cells/metabolism
• Neural Stem Cells/cytology
• Mice
• Corpus Striatum/cytology
• Corpus Striatum/metabolism
• Cell Differentiation
• Mice, Inbred C57BL
• Stem Cell Niche
• Lateral Ventricles/cytology

• Adult neurogenesis
• Cell cycle
• Neural stem/progenitor cells
• Subventricular zone
• Transcriptional regulation

• Animals
• Mice
• Aging/genetics
• Cell Division
• Genes, Homeobox
• Neurogenesis/genetics
• Neurons
• Transcription Factors

• MR/T011769/1 Medical Research Council
• BBS/E/B/000C0421 Biotechnology and Biological Sciences Research Council
• Sapienza Università di Roma
• Università degli Studi di Roma La Sapienza

• adult hippocampal neurogenesis
• adult neural stem cells
• aging
• intrinsic mechanisms
• neurogenic niche
• rejuvenation
• systemic environment

• Animals
• Rats
• Neurogenesis
• Adult Stem Cells
• Aging
• Hippocampus
• Neural Stem Cells

• Mechanistic models
• Neurogenesis
• Population models
• Single-cell data
• Stem cells

• aging
• exercise
• hematopoietic stem cells
• inflammation
• muscle stem cells
• myofibers
• neural stem cells
• scRNA-seq
• skeletal muscle
• subventricular zone

• Mice
• Animals
• Aging/physiology
• Hematopoietic Stem Cells
• Physical Conditioning, Animal
• Transcriptome/genetics
• Gene Expression Profiling
• Muscle, Skeletal
• Stem Cell Niche
• Mammals

• S10 OD025212 NIH HHS
• R01 AG071783 NIA NIH HHS
• R01 HL126527 NHLBI NIH HHS
• R01 AG047820 NIA NIH HHS
• P01 AG036695 NIA NIH HHS
• R01 AR073248 NIAMS NIH HHS
• P30 CA125123 NCI NIH HHS
• R01 HL130020 NHLBI NIH HHS
• R37 AG023806 NIA NIH HHS
• P30 DK116074 NIDDK NIH HHS
• R01 AG068667 NIA NIH HHS
• I01 BX002324 BLRD VA
• R01 DK092883 NIDDK NIH HHS

The ability of adult neural stem cells to produce new neurons (neurogenesis) declines markedly during aging, but exactly how this occurs is largely unknown. Using sophisticated in vivo imaging, a study in Nature Aging shows that aging affects several steps of neurogenesis — most notably, increasing the death of newborn clones.

• P01 AG036695 NIA NIH HHS
• T32 GM007365 NIGMS NIH HHS

• Rejuvenation
• Stem Cells
• Cellular Senescence/physiology
• Cell Differentiation
• Stem Cell Niche

• P01 AG036695 NIA NIH HHS
• R01 AG071711 NIA NIH HHS
• R01 AG071783 NIA NIH HHS

• cell biology
• ageing

• Animals
• Mice
• Cell Proliferation
• Src Homology 2 Domain-Containing, Transforming Protein 1/genetics
• Src Homology 2 Domain-Containing, Transforming Protein 1/metabolism
• Stem Cells/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Mammary Glands, Animal/cytology

• Fondazione Italiana per la Ricerca sul Cancro (Italian Foundation for Cancer Research)
• Fondazione Umberto Veronesi (Umberto Veronesi Foundation)
• Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research) - AIRC-IG-2014-20162
• Fondazione Cariplo 2016-1031

Maternal obesity or exposure to a high-fat diet (HFD) has an irreversible impact on the structural and functional development of offspring brains. This study aimed to investigate whether maternal HFD during pregnancy and lactation impairs dentate gyrus (DG) neurogenesis in offspring by altering neural stem cells (NSCs) behaviors. Pregnant Sprague-Dawley rats were fed a chow diet (CHD) or HFD (60% fat) during gestation and lactation. Pups were collected on postnatal day 1 (PND 1), PND 10 and PND 21. Changes in offspring body weight, brain structure and granular cell layer (GCL) thickness in the hippocampus were analyzed. Hippocampal NSCs behaviors, in terms of proliferation and differentiation, were investigated after immunohistochemical staining with Nestin, Ki67, SOX2, Doublecortin (DCX) and NeuN. Maternal HFD accelerated body weight gain and brain structural development in offspring after birth. It also reduced the number of NSCs and their proliferation, leading to a decrease in NSCs pool size. Furthermore, maternal HFD intensified NSCs depletion and promoted neuronal differentiation in the early postnatal development period. These findings suggest that maternal HFD intake significantly reduced the amount and capability of NSCs via reducing type–2 NSCs and promoting premature neuronal differentiation during postnatal hippocampal development.

• dentate gyrus
• early postnatal period
• maternal high-fat diet
• neural stem cells behavior
• neuronal differentiation

• Animals
• Body Weight
• Diet, High-Fat/adverse effects
• Female
• Humans
• Neural Stem Cells
• Neurogenesis
• Pregnancy
• Prenatal Exposure Delayed Effects
• Rats
• Rats, Sprague-Dawley

Robust brain development requires the tight coordination between tissue growth, neuronal differentiation and stem cell maintenance. To achieve this, neural stem cells need to balance symmetric proliferative and terminal divisions with asymmetric divisions. In recent years, the unequal distribution of certain cellular components in mitosis has emerged as a key mechanism to regulate the symmetry of division, and the determination of equal and unequal sister cell fates. Examples of such components include polarity proteins, signaling components, and cellular structures such as endosomes and centrosomes. In several types of neural stem cells, these factors show specific patterns of inheritance that correlate to specific cell fates, albeit the underlying mechanism and the potential causal relationship is not always understood. Here, we review these examples of cellular neural stem and progenitor cell asymmetries and will discuss how they fit into our current understanding of neural stem cell function in neurogenesis in developing and adult brains. We will focus mainly on the vertebrate brain, though we will incorporate relevant examples from invertebrate organisms as well. In particular, we will highlight recent advances in our understanding of the complexities related cellular asymmetries in determining division mode outcomes, and how these mechanisms are spatiotemporally regulated to match the different needs for proliferation and differentiation as the brain forms.

• Rijksuniversiteit Groningen

Neurogenesis persists in selected regions of the adult mouse brain; among them, the ventricular-subventricular zone (V-SVZ) of the lateral ventricles represents a major experimental paradigm due to its conspicuous neurogenic output. Postnatal V-SVZ neurogenesis is maintained by a resident population of neural stem cells (NSCs). Although V-SVZ NSCs are largely quiescent, they can be activated to enter the cell cycle, self-renew and generate progeny that gives rise to olfactory bulb interneurons. These adult-born neurons integrate into existing circuits to modify cognitive functions in response to external stimuli, but cells shed by V-SVZ NSCs can also reach injured brain regions, suggesting a latent regenerative potential. The V-SVZ is endowed with a specialized microenvironment, which is essential to maintain the proliferative and neurogenic potential of NSCs, and to preserve the NSC pool from exhaustion by finely tuning their quiescent and active states. Intercellular communication is paramount to the stem cell niche properties of the V-SVZ, and several extracellular signals acting in the niche milieu have been identified. An important part of these signals comes from non-neural cell types, such as local vascular cells, ependymal and glial cells. Understanding the crosstalk between NSCs and other niche components may aid therapeutic approaches for neuropathological conditions, since neurodevelopmental disorders, age-related cognitive decline and neurodegenerative diseases have been associated with dysfunctional neurogenic niches. Here, we review recent advances in the study of the complex interactions between V-SVZ NSCs and their cellular niche. We focus on the extracellular cues produced by ependymal and vascular cells that regulate NSC behavior in the mouse postnatal V-SVZ, and discuss the potential implication of these molecular signals in pathological conditions.

• Ministero degli Affari Esteri e della Cooperazione Internazionale

Understanding the generation of complexity in living organisms requires the use of lineage tracing tools at a multicellular scale. In this review, we describe the different multicolor strategies focusing on mouse models expressing several fluorescent reporter proteins, generated by classical (MADM, Brainbow and its multiple derivatives) or acute (StarTrack, CLoNe, MAGIC Markers, iOn, viral vectors) transgenesis. After detailing the multi-reporter genetic strategies that serve as a basis for the establishment of these multicolor mouse models, we briefly mention other animal and cellular models (zebrafish, chicken, drosophila, iPSC) that also rely on these constructs. Then, we highlight practical applications of multicolor mouse models to better understand organogenesis at single progenitor scale (clonal analyses) in the brain and briefly in several other tissues (intestine, skin, vascular, hematopoietic and immune systems). In addition, we detail the critical contribution of multicolor fate mapping strategies in apprehending the fine cellular choreography underlying tissue morphogenesis in several models with a particular focus on brain cytoarchitecture in health and diseases. Finally, we present the latest technological advances in multichannel and in-depth imaging, and automated analyses that enable to better exploit the large amount of data generated from multicolored tissues.

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.

• adult neurogenesis
• cell heterogeneity
• cell lineage tracing
• clonal analysis
• neural progenitors
• neural stem cells
• self-renewal
• transcriptomics

• ATAC-seq
• Ascl1
• ChIP-seq
• Dyrk1a
• Plagl2
• adult neurogenesis
• aged brain
• lentivirus
• mouse
• neural stem cell

• Animals
• Hippocampus
• Mice
• Neural Stem Cells
• Neurogenesis/genetics
• Neurons
• Rejuvenation

• Core Research for Evolutional Science and Technology
• Japan Agency for Medical Research and Development
• Japan Society for the Promotion of Science

Cerebral (“brain”) organoids are high-fidelity in vitro cellular models of the developing brain, which makes them one of the go-to methods to study isolated processes of tissue organization and its electrophysiological properties, allowing to collect invaluable data for in silico modeling neurodevelopmental processes. Complex computer models of biological systems supplement in vivo and in vitro experimentation and allow researchers to look at things that no laboratory study has access to, due to either technological or ethical limitations. In this paper, we present the Biological Cellular Neural Network Modeling (BCNNM) framework designed for building dynamic spatial models of neural tissue organization and basic stimulus dynamics. The BCNNM uses a convenient predicate description of sequences of biochemical reactions and can be used to run complex models of multi-layer neural network formation from a single initial stem cell. It involves processes such as proliferation of precursor cells and their differentiation into mature cell types, cell migration, axon and dendritic tree formation, axon pathfinding and synaptogenesis. The experiment described in this article demonstrates a creation of an in silico cerebral organoid-like structure, constituted of up to 1 million cells, which differentiate and self-organize into an interconnected system with four layers, where the spatial arrangement of layers and cells are consistent with the values of analogous parameters obtained from research on living tissues. Our in silico organoid contains axons and millions of synapses within and between the layers, and it comprises neurons with high density of connections (more than 10). In sum, the BCNNM is an easy-to-use and powerful framework for simulations of neural tissue development that provides a convenient way to design a variety of tractable in silico experiments.

• axon guidance
• brain organoid
• neurogenesis
• neuronal connectivity
• simulation
• tissue development

The production of neurons from neural stem cells (NSCs) persists throughout life in the mouse ventricular-subventricular zone (V-SVZ). We have previously reported that NSCs from adult V-SVZ are contained in cell populations expressing the carbohydrate SSEA-1/LeX, which exhibit either characteristics of quiescent NSCs (qNSCs) or of actively dividing NSCs (aNSCs) based on the absence or the presence of EGF-receptor, respectively. Using the fluorescence ubiquitination cell cycle indicator-Cdt1 transgenic mice to mark cells in G₀/G₁ phase of the cell cycle, we uncovered a subpopulation of qNSCs which were primed to enter the cell cycle in vitro. Besides, we found that treatment with Syndecan-1, a heparan sulfate proteoglycan involved in NSC proliferation, hastened the division of qNSCs and increased proliferation of aNSCs shortening their G₁ phase in vitro. Furthermore, administration of Syndecan-1 ameliorated the recovery of neurogenic populations in the V-SVZ after radiation-induced injury providing potential cure for neurogenesis decline during brain aging or after injury.

•

A subpopulation of quiescent NSCs are primed to enter cell cycle

• Neuroscience
• Stem Cell Research

• dynamic homeostasis
• intrinsic niche
• neural stem cell
• population behavior
• spatiotemporal coordination
• zebrafish

Adult neurogenesis, i.e., the generation of neurons from neural stem cells (NSCs) in the adult brain, contributes to brain plasticity in all vertebrates. It varies, however, greatly in extent, location and physiological characteristics between species. During the last decade, the teleost zebrafish (D. rerio) was increasingly used to study the molecular and cellular properties of adult NSCs, in particular as a prominent NSC population was discovered at the ventricular surface of the dorsal telencephalon (pallium), in territories homologous to the adult neurogenic niches of rodents. This model, for its specific features (large NSC population, amenability to intravital imaging, high regenerative capacity) allowed rapid progress in the characterization of basic adult NSC features. We review here these findings, with specific comparisons with the situation in rodents. We specifically discuss the cellular nature of NSCs (astroglial or neuroepithelial cells), their heterogeneities and their neurogenic lineages, and the mechanisms controlling NSC quiescence and fate choices, which all impact the neurogenic output. We further discuss the regulation of NSC activity in response to physiological triggers and non-physiological conditions such as regenerative contexts.

• adult neurogenesis
• cell fate choice decisions
• neural stem cell
• pallium
• quiescence
• radial glia
• zebrafish

• Gecko
• Mouse
• Neural stem cells
• Single sphere RNA-Seq
• Spinal cord

• aging
• granulin
• microglia
• neurogenesis

• Aging/metabolism
• Aging, Premature/genetics
• Animals
• Cell Differentiation
• Gene Expression Profiling
• Intercellular Signaling Peptides and Proteins/deficiency
• Intercellular Signaling Peptides and Proteins/metabolism
• Kinetics
• Microglia/metabolism
• Microglia/pathology
• Mutation/genetics
• Neurogenesis/genetics
• Oligodendroglia/metabolism
• Phenotype
• Stem Cells/metabolism
• Telencephalon/metabolism
• Telomere/metabolism
• Transcriptome/genetics
• Zebrafish/genetics
• Zebrafish/metabolism
• Zebrafish Proteins/deficiency
• Zebrafish Proteins/metabolism

Poor recovery of neuronal functions is one of the most common healthcare challenges for patients with different types of brain injuries and/or neurodegenerative diseases. Therapeutic interventions face two major challenges: (1) How to generate neurons de novo to replenish the neuronal loss caused by injuries or neurodegeneration (restorative neurogenesis) and (2) How to prevent or limit the secondary tissue damage caused by long-term accumulation of glial cells, including microglia, at injury site (glial scar). In contrast to mammals, zebrafish have extensive regenerative capacity in numerous vital organs, including the brain, thus making them a valuable model to improve the existing therapeutic approaches for human brain repair. In response to injuries to the central nervous system (CNS), zebrafish have developed specific mechanisms to promote the recovery of the lost tissue architecture and functionality of the damaged CNS. These mechanisms include the activation of a restorative neurogenic program in a specific set of glial cells (ependymoglia) and the resolution of both the glial scar and inflammation, thus enabling proper neuronal specification and survival. In this review, we discuss the cellular and molecular mechanisms underlying the regenerative ability in the adult zebrafish brain and conclude with the potential applicability of these mechanisms in repair of the mammalian CNS.

• Zebrafish
• Central nervous system
• Brain injury
• Glial scar
• Regeneration
• Restorative neurogenesis
• Neural stem cells
• Inflammation

In rodents, well characterized neurogenic niches of the adult brain, such as the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus, support the maintenance of neural/stem progenitor cells (NSPCs) and the production of new neurons throughout the lifespan. The adult neurogenic process is dependent on the intrinsic gene expression signatures of NSPCs that make them competent for self-renewal and neuronal differentiation. At the same time, it is receptive to regulation by various extracellular signals that allow the modulation of neuronal production and integration into brain circuitries by various physiological stimuli. A drawback of this plasticity is the sensitivity of adult neurogenesis to alterations of the niche environment that can occur due to aging, injury or disease. At the core of the molecular mechanisms regulating neurogenesis, several transcription factors have been identified that maintain NSPC identity and mediate NSPC response to extrinsic cues. Here, we focus on REST, Egr1 and Dbx2 and their roles in adult neurogenesis, especially in the subventricular zone. We review recent work from our and other laboratories implicating these transcription factors in the control of NSPC proliferation and differentiation and in the response of NSPCs to extrinsic influences from the niche. We also discuss how their altered regulation may affect the neurogenic process in the aged and in the diseased brain. Finally, we highlight key open questions that need to be addressed to foster our understanding of the transcriptional mechanisms controlling adult neurogenesis.

• adult neurogenesis
• aging
• extracellular signaling
• gene regulation
• neural stem/progenitor cells
• transcription factors

In the mammalian adult brain, neural stem cells persist in neurogenic niches. The subependymal zone is the most prolific neurogenic niche in adult rodents, where residing stem cells generate large numbers of immature neurons that migrate into the olfactory bulb, where they differentiate into different types of interneurons. Subependymal neural stem cells derive from embryonic radial glia and retain some of their features like apico-basal polarity, with apical processes piercing the ependymal layer, and a basal process contacting blood vessels, constituting an epithelial niche. Conservation of the cytoarchitecture of the niche is of crucial importance for the maintenance of stem cells and for their neurogenic potential. In this minireview we will focus on extracellular matrix and adhesion molecules in the adult subependymal zone, showing their involvement not only as structural elements sustaining the niche architecture and topology, but also in the maintenance of stemness and regulation of the quiescence-proliferation balance.

• adhesion molecules
• adult neurogenesis
• extracellular matrix
• neural stem cell
• niche
• quiescence
• subependymal zone

Neurodegenerative diseases are devastating medical conditions with no effective treatments. Restoration of impaired neurogenesis represents a promising therapeutic strategy for neurodegenerative diseases. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein that plays a wide range of cellular functions including phagocytosis of apoptotic cells, anti-inflammation, tissue regeneration, and homeostasis. The beneficial role of MFG-E8 has been shown in cerebral ischemia (stroke), neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, and traumatic brain injury. In stroke, MFG-E8 promotes neural stem cell proliferation and their migration toward the ischemic brain tissues. These novel functions of MFG-E8 are primarily mediated through its receptor α_vβ₃-integrin. Here, we focus on the pivotal role of MFG-E8 in protecting against neuronal diseases by promoting neurogenesis. We also discuss the mechanisms of MFG-E8-mediated neural stem/progenitor cell (NSPC) proliferation and migration, and the potential of MFG-E8 for neural stem cell niche maintenance via angiogenesis. We propose further investigation of the molecular pathways for MFG-E8 signaling in NSPC and effective strategies for MFG-E8 delivery across the blood–brain barrier, which will help develop MFG-E8 as a future drug candidate for the bedside management of neurodegenerative diseases.

• Alzheimer’s disease
• MFG-E8
• Parkinson’s disease
• apoptosis
• integrin
• neurodegenerative diseases
• neurogenesis
• stem cells

In the adult rodent brain, the continuous production of new neurons by neural stem/progenitor cells (NSPCs) residing in specialized neurogenic niches and their subsequent integration into pre-existing cerebral circuitries supports odour discrimination, spatial learning, and contextual memory capabilities. Aging is recognized as the most potent negative regulator of adult neurogenesis. The neurogenic process markedly declines in the aged brain, due to the reduction of the NSPC pool and the functional impairment of the remaining NSPCs. This decline has been linked to the progressive cognitive deficits of elderly individuals and it may also be involved in the onset/progression of neurological disorders. Since the human lifespan has been dramatically extended, the incidence of age-associated neuropsychiatric conditions in the human population has increased. This has prompted efforts to shed light on the mechanisms underpinning the age-related decline of adult neurogenesis, whose knowledge may foster therapeutic approaches to prevent or delay cognitive alterations in elderly patients. In this review, we summarize recent progress in elucidating the molecular causes of neurogenic aging in the most abundant NSPC niche of the adult mouse brain: the subventricular zone (SVZ). We discuss the age-associated changes occurring both in the intrinsic NSPC molecular networks and in the extrinsic signalling pathways acting in the complex environment of the SVZ niche, and how all these changes may steer young NSPCs towards an aged phenotype.

• Adult neurogenesis
• aging
• neural stem/progenitor cells
• niche
• tumour suppressor pathways