Neural stem cells-from quiescence to differentiation and potential clinical uses

Specialised cells of the brain are generated from a population of multipotent stem cells found in the forming embryo and adult brain after birth, called neural stem cells. They reside in specific niches, usually in a quiescent, non-proliferating state that maintains their reservoir. Neural stem cells are kept inactive by various cues such as direct cell-cell contacts with neighbouring cells or by soluble molecules that trigger intracellular responses. They are activated in response to injuries, physical exercise, or hypoxia condition, through stimulation of signaling pathways that are usually correlated with increased proliferation and survival. Moreover, mature neurons play essential role in regulating the balance between active and quiescent state by realising inhibitory or activating neurotransmitters. Understanding molecular mechanisms underlying neuronal differentiation is of great importance in elucidating pathological conditions of the brain and treating neurodegenerative disorders that until now have no efficient therapies.

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Brain tumor stem cells

Biological Chemistry ◽

10.1515/bc.2010.059 ◽

2010 ◽

Vol 391 (6) ◽

Cited By ~ 7

Author(s):

Thomas Palm ◽

Jens C. Schwamborn

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Neural Stem Cells ◽

Molecular Mechanisms ◽

Adult Brain ◽

Tumor Stem Cells ◽

Cellular Mechanisms ◽

Cell Pool ◽

Brain Tumor Stem Cells ◽

Stem Cell Pool

Abstract Since the end of the ‘no-new-neuron’ theory, emerging evidence from multiple studies has supported the existence of stem cells in neurogenic areas of the adult brain. Along with this discovery, neural stem cells became candidate cells being at the origin of brain tumors. In fact, it has been demonstrated that molecular mechanisms controlling self-renewal and differentiation are shared between brain tumor stem cells and neural stem cells and that corruption of genes implicated in these pathways can direct tumor growth. In this regard, future anticancer approaches could be inspired by uncovering such redundancies and setting up treatments leading to exhaustion of the cancer stem cell pool. However, deleterious effects on (normal) neural stem cells should be minimized. Such therapeutic models underline the importance to study the cellular mechanisms implicated in fate decisions of neural stem cells and the oncogenic derivation of adult brain cells. In this review, we discuss the putative origins of brain tumor stem cells and their possible implications on future therapies.

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Adult Neurogenesis: Lessons from Crayfish and the Elephant in the Room

Brain Behavior and Evolution ◽

10.1159/000447084 ◽

2016 ◽

Vol 87 (3) ◽

pp. 146-155 ◽

Cited By ~ 3

Author(s):

Barbara S. Beltz ◽

Georg Brenneis ◽

Jeanne L. Benton

Keyword(s):

Stem Cells ◽

Immune System ◽

Neural Stem Cells ◽

Adult Neurogenesis ◽

Adult Brain ◽

Neural Precursor ◽

Neural Precursors ◽

Neurogenic Niche ◽

Fetal Microchimerism ◽

The Brain

The 1st-generation neural precursors in the crustacean brain are functionally analogous to neural stem cells in mammals. Their slow cycling, migration of their progeny, and differentiation of their descendants into neurons over several weeks are features of the neural precursor lineage in crayfish that also characterize adult neurogenesis in mammals. However, the 1st-generation precursors in crayfish do not self-renew, contrasting with conventional wisdom that proposes the long-term self-renewal of adult neural stem cells. Nevertheless, the crayfish neurogenic niche, which contains a total of 200-300 cells, is never exhausted and neurons continue to be produced in the brain throughout the animal's life. The pool of neural precursors in the niche therefore cannot be a closed system, and must be replenished from an extrinsic source. Our in vitro and in vivo data show that cells originating in the innate immune system (but not other cell types) are attracted to and incorporated into the neurogenic niche, and that they express a niche-specific marker, glutamine synthetase. Further, labeled hemocytes that undergo adoptive transfer to recipient crayfish generate cells in neuronal clusters in the olfactory pathway of the adult brain. These hemocyte descendants express appropriate neurotransmitters and project to target areas typical of neurons in these regions. These studies indicate that under natural conditions, the immune system provides neural precursors supporting adult neurogenesis in the crayfish brain, challenging the canonical view that ectodermal tissues generating the embryonic nervous system are the sole source of neurons in the adult brain. However, these are not the first studies that directly implicate the immune system as a source of neural precursor cells. Several types of data in mammals, including adoptive transfers of bone marrow or stem cells as well as the presence of fetal microchimerism, suggest that there must be a population of cells that are able to access the brain and generate new neurons in these species.

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DNA Methylation Abnormality and Brain Dysfunction of Neural Stem Cells Caused by Chronic Inflammation by Nanoparticle Exposure

Impact ◽

10.21820/23987073.2020.7.28 ◽

2020 ◽

Vol 2020 (7) ◽

pp. 28-30

Author(s):

Ken Tachibana

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neural Development ◽

Broad Class ◽

Cell Types ◽

Associate Professor ◽

Adult Brain ◽

Wide Range ◽

The Creation ◽

The Brain

The biological development of a human is an extremely complex and delicate process. It starts from fertilisation and continues until long after birth. The creation and development of the brain is particularly complicated and susceptible to disruptions to its progression. The primary cells responsible for the development of the brain are the neural stem cells. These are a broad class of cells that can differentiate into the wide range of cell types that form the adult brain. To achieve this complex process, different cells need to undergo a range of gene expression changes at the right time. This is delicate and its disturbance is a key cause of pathology in a wide range of diseases. There are many external factors that are known to disrupt neural development however, there are several common chemicals whose effects remain largely unknown. One such group are broadly described as nanoparticles. These are small particles that are being increasingly used by many industries as they can help in the creation of products with better properties. However, their effect on the environment and the human body – particularly that of a developing brain – have been largely unexamined. Associate Professor Ken Tachibana of the Division of Hygienic Chemistry, Sanyo-Onoda City University, Japan is researching the effects of nanoparticles on neural development.

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Enhanced lysosomal degradation maintains the quiescent state of neural stem cells

Nature Communications ◽

10.1038/s41467-019-13203-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Taeko Kobayashi ◽

Wenhui Piao ◽

Toshiya Takamura ◽

Hiroshi Kori ◽

Hitoshi Miyachi ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Membrane Trafficking ◽

Egf Receptor ◽

Membrane Receptors ◽

Adult Brain ◽

Conditional Knockout ◽

Quiescent State ◽

Lysosomal Degradation

AbstractQuiescence is important for sustaining neural stem cells (NSCs) in the adult brain over the lifespan. Lysosomes are digestive organelles that degrade membrane receptors after they undergo endolysosomal membrane trafficking. Enlarged lysosomes are present in quiescent NSCs (qNSCs) in the subventricular zone of the mouse brain, but it remains largely unknown how lysosomal function is involved in the quiescence. Here we show that qNSCs exhibit higher lysosomal activity and degrade activated EGF receptor by endolysosomal degradation more rapidly than proliferating NSCs. Chemical inhibition of lysosomal degradation in qNSCs prevents degradation of signaling receptors resulting in exit from quiescence. Furthermore, conditional knockout of TFEB, a lysosomal master regulator, delays NSCs quiescence in vitro and increases NSC proliferation in the dentate gyrus of mice. Taken together, our results demonstrate that enhanced lysosomal degradation is an important regulator of qNSC maintenance.

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Effects of Radiation Therapy on Neural Stem Cells

Genes ◽

10.3390/genes10090640 ◽

2019 ◽

Vol 10 (9) ◽

pp. 640 ◽

Cited By ~ 6

Author(s):

Anna Michaelidesová ◽

Jana Konířová ◽

Petr Bartůněk ◽

Martina Zíková

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Side Effects ◽

Neural Stem Cells ◽

Neural Stem Cell ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Brain Radiotherapy ◽

The Impact ◽

The Brain

Brain and nervous system cancers in children represent the second most common neoplasia after leukemia. Radiotherapy plays a significant role in cancer treatment; however, the use of such therapy is not without devastating side effects. The impact of radiation-induced damage to the brain is multifactorial, but the damage to neural stem cell populations seems to play a key role. The brain contains pools of regenerative neural stem cells that reside in specialized neurogenic niches and can generate new neurons. In this review, we describe the advances in radiotherapy techniques that protect neural stem cell compartments, and subsequently limit and prevent the occurrence and development of side effects. We also summarize the current knowledge about neural stem cells and the molecular mechanisms underlying changes in neural stem cell niches after brain radiotherapy. Strategies used to minimize radiation-related damages, as well as new challenges in the treatment of brain tumors are also discussed.

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Modelling glioblastoma tumour-host cell interactions using adult brain organotypic slice co-culture

10.1101/166967 ◽

2017 ◽

Author(s):

Maria Angeles Marques-Torrejon ◽

Ester Gangoso ◽

Steven M. Pollard

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cells ◽

Neural Stem Cell ◽

Ex Vivo ◽

Brain Slices ◽

Genetically Engineered ◽

Adult Brain ◽

Host Interactions ◽

The Brain

AbstractGlioblastoma (GBM) is an aggressive incurable brain cancer. The cells that fuel the growth of tumours resemble neural stem cells found in the developing and adult mammalian forebrain. These are referred to as GBM stem cells (GSCs). Similar to neural stem cells, GSCs exhibit a variety of phenotypic states: dormant, quiescent, proliferative and differentiating. How environmental cues within the brain influence these distinct states is not well understood. Laboratory models of GBM tumours can be generated using either genetically engineered mouse models, or via intracranial transplantation of cultured tumour initiating cells (mouse or human). Unfortunately, these approaches are expensive, time-consuming, low-throughput and ill-suited for monitoring of live cell behaviours. Here we explored whole adult brain coronal organotypic slices as a complementary strategy to remove the experimental bottleneck. Mouse adult brain slices remain viable in a neural stem cell serum-free basal media for several weeks. GSCs can therefore be easily microinjected into specific anatomical sites ex vivo. We demonstrated distinct responses of engrafted GSCs to different microenvironments in the brain. Within the subependymal zone – one of the adult neural stem cell niches – a subset of injected tumour cells could effectively engraft and respond to endothelial niche signals. GSCs transplanted slices were treated with the anti-mitotic drug temozolomide as proof-of-principle of the utility in modelling responses to existing treatments. Thus, engraftment of mouse or human GSCs onto whole brain coronal organotypic brain slices provides a convenient experimental model for studies of GSC-host interactions and preclinical testing of candidate therapeutic agents.

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Neurogenesis-An Overview

Journal of Regenerative Biology and Medicine ◽

10.37191/mapsci-2582-385x-3(6)-091 ◽

2021 ◽

Author(s):

Blossom Samuel Affia

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Adult Neurogenesis ◽

Adult Brain ◽

Long Time ◽

The One ◽

The Brain ◽

Different Parts

Neurogenesis is a phenomenon that involves the formation of new neurons in the brain by neural stem cells (NSCs). Investigators have confirmed that neurogenesis occurs in discrete parts of the adult brain as opposed to the embryos [1]. However, this was not the case long time back. Researchers have always been interested in learning if humans or other large organisms could show regenerative properties like the one seen in specific small organisms which can regrow different parts of their own bodies [2]. If possible, this would lead to a new avenue in therapeutics as more scientists would try to stimulate regeneration to deal with injury or any harmful stimuli. Like mentioned previously, researchers were not convinced with this approach and deemed that there is no possibility of adult neurogenesis [3].

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Stem cells in stroke management

Reviews in Clinical Gerontology ◽

10.1017/s0959259810000390 ◽

2010 ◽

Vol 21 (2) ◽

pp. 125-140

Author(s):

Keith W Muir

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Tissue Regeneration ◽

Clinical Studies ◽

Cell Types ◽

Adult Brain ◽

Permanent Disability ◽

Ischaemic Injury ◽

Cell Therapies ◽

The Brain

SummaryStem cells are a potential means of tissue regeneration in the brain that hold promise for treatment of the large number of stroke survivors who have permanent disability. Animal studies with stem cells derived from many different sources indicate that cells can migrate to the site of ischaemic injury in the brain, and that some survive and differentiate into neurones and glia with evidence of electrical function. Cells additionally promote endogenous repair mechanisms, including mobilization of neural stem cells resident within the adult brain. Whether the behavioural benefits seen with stem cell administration in rodent models reflect enhanced endogenous recovery or tissue regeneration is unclear. Production of stem cells to clinical standards and in quantities required for clinical studies is technically challenging. To date only a handful of patients have been involved in preliminary clinical studies of cell therapies for stroke, and there are therefore insufficient data to draw conclusions about either safety or efficacy. Further trials with several cell types are ongoing or planned, including neural stem cells, and bone marrow-derived stem cells and endothelial progenitor cells.

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