Neural stem cell
Neural stem cell | |
---|---|
Details | |
System | Nervous system |
Identifiers | |
Latin | cellula nervosa praecursoria |
MeSH | D058953 |
TH | H2.00.01.0.00010 |
FMA | 86684 |
Anatomical terms of microanatomy |
Neural stem cells (NSCs) are self-renewing,
Stem cells are characterized by their capacity to differentiate into multiple cell types.[3] They undergo symmetric or asymmetric cell division into two daughter cells. In symmetric cell division, both daughter cells are also stem cells. In asymmetric division, a stem cell produces one stem cell and one specialized cell.[4] NSCs primarily differentiate into neurons, astrocytes, and oligodendrocytes.
Brain location
In the adult mammalian brain, the subgranular zone in the hippocampal dentate gyrus, the subventricular zone around the lateral ventricles, and the hypothalamus (precisely in the dorsal α1, α2 region and the "hypothalamic proliferative region”, located in the adjacent median eminence) have been reported to contain neural stem cells.[5]
Development
In vivo origin
There are two basic types of stem cell:
Neural stem cells are more specialized than ESCs because they only generate
In vitro origin
Adult NSCs were first isolated from mouse
Communication and migration
NSCs are stimulated to begin differentiation via exogenous cues from the microenvironment, or stem cell niche. Some neural cells are migrated from the SVZ along the
Aging
Neural stem cell proliferation declines as a consequence of aging.[9] Various approaches have been taken to counteract this age-related decline.[10] Because FOX proteins regulate neural stem cell homeostasis,[11] FOX proteins have been used to protect neural stem cells by inhibiting Wnt signaling.[12]
Function
Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth.[13] It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.
During differentiation
The most widely accepted model of an adult NSC is a radial, glial fibrillary acidic protein-positive cell. Quiescent stem cells are Type B that are able to remain in the quiescent state due to the renewable tissue provided by the specific niches composed of blood vessels, astrocytes, microglia, ependymal cells, and extracellular matrix present within the brain. These niches provide nourishment, structural support, and protection for the stem cells until they are activated by external stimuli. Once activated, the Type B cells develop into Type C cells, active proliferating intermediate cells, which then divide into neuroblasts consisting of Type A cells. The undifferentiated neuroblasts form chains that migrate and develop into mature neurons. In the olfactory bulb, they mature into GABAergic granule neurons, while in the hippocampus they mature into dentate granule cells.[14]
Epigenetic modification
These types of modification are critical for cell fate determination in the developing and adult mammalian brain.During disease
NSCs have an important role during development producing the enormous diversity of neurons, astrocytes and oligodendrocytes in the developing CNS. They also have important role in adult animals, for instance in learning and hippocampal plasticity in the adult mice in addition to supplying neurons to the olfactory bulb in mice.[7]
Notably the role of NSCs during diseases is now being elucidated by several research groups around the world. The responses during stroke, multiple sclerosis, and Parkinson's disease in animal models and humans is part of the current investigation. The results of this ongoing investigation may have future applications to treat human neurological diseases.[7]
Neural stem cells have been shown to engage in migration and replacement of dying
The search for additional mechanisms that operate in the injury environment and how they influence the responses of NSCs during acute and chronic disease is matter of intense research.[20]
Research
Regenerative therapy of the CNS
Cell death is a characteristic of acute CNS disorders as well as neurodegenerative disease. The loss of cells is amplified by the lack of regenerative abilities for cell replacement and repair in the CNS. One way to circumvent this is to use cell replacement therapy via regenerative NSCs. NSCs can be cultured in vitro as neurospheres. These neurospheres are composed of neural stem cells and progenitors (NSPCs) with growth factors such as EGF and FGF. The withdrawal of these growth factors activate differentiation into neurons, astrocytes, or oligodendrocytes which can be transplanted within the brain at the site of injury. The benefits of this therapeutic approach have been examined in Parkinson's disease, Huntington's disease, and multiple sclerosis. NSPCs induce neural repair via intrinsic properties of neuroprotection and immunomodulation. Some possible routes of transplantation include intracerebral transplantation and xenotransplantation.[21][22]
For neurodegenerative diseases, another transplantation therapy arising in research is the directional induction of neural stem cells.[23] The direct transplantation of NCSs is limited and faces challenges due to low survival rate and irrational differentiation. To overcome the limitations, the direct induction of NCSs aims to manipulate the differentiation of NCS prior to transplantation. Currently NSCs are obtained from primary CNS tissues, the differentiation of pluripotent stem cells (PSC) and transdifferentiation from somatic cells. Induced NCSs can be reprogrammed from somatic cells. Hence, directional induction takes NSCs from different sources and forces them to differentiate into the desired neural lineage cells. An example of the therapeutic usage of this technique is the targeted differentiation of ventral midbrain dopaminergic (DAergenic) neurons into different models of PD.[23] Current therapies for the neurodegenerative disease Parkinson’s Disease (PD) include dopamine replacement therapy (DRT). This works to alleviate PD symptoms, but as the disease progresses, the alleviating mechanisms are affected in a nonlinear manner.[24]
An alternative therapeutic approach to the transplantation of NSPCs is the pharmacological activation of endogenous NSPCs (eNSPCs). Activated eNSPCs produce neurotrophic factors, several treatments that activate a pathway that involves the phosphorylation of STAT3 on the serine residue and subsequent elevation of Hes3 expression (STAT3-Ser/Hes3 Signaling Axis) oppose neuronal death and disease progression in models of neurological disorder.[25][26]
Generation of 3D in vitro models of the human CNS
Human
Bioactive scaffolds as traumatic brain injury treatment
Galectin-1 in neural stem cells
Galectin-1 is expressed in adult NSCs and has been shown to have a physiological role in the treatment of neurological disorders in animal models. There are two approaches to using NSCs as a therapeutic treatment: (1) stimulate intrinsic NSCs to promote proliferation in order to replace injured tissue, and (2) transplant NSCs into the damaged brain area in order to allow the NSCs to restore the tissue. Lentivirus vectors were used to infect human NSCs (hNSCs) with Galectin-1 which were later transplanted into the damaged tissue. The hGal-1-hNSCs induced better and faster brain recovery of the injured tissue as well as a reduction in motor and sensory deficits as compared to only hNSC transplantation.[8]
Assays
Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or Neurosphere culture system), first developed by Reynolds and Weiss.[30] Neurospheres are intrinsically heterogeneous cellular entities almost entirely formed by a small fraction (1 to 5%) of slowly dividing neural stem cells and by their progeny, a population of fast-dividing nestin-positive progenitor cells.[30][31][32] The total number of these progenitors determines the size of a neurosphere and, as a result, disparities in sphere size within different neurosphere populations may reflect alterations in the proliferation, survival and/or differentiation status of their neural progenitors. Indeed, it has been reported that loss of β1-integrin in a neurosphere culture does not significantly affect the capacity of β1-integrin deficient stem cells to form new neurospheres, but it influences the size of the neurosphere: β1-integrin deficient neurospheres were overall smaller due to increased cell death and reduced proliferation.[33]
While the Neurosphere Assay has been the method of choice for isolation, expansion and even the enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the limitations of the neurosphere culture system as a method for determining neural stem cell frequencies.
History
The first evidence that neurogenesis occurs in certain regions of the adult mammalian brain came from [3H]-thymidine labeling studies conducted by Altman and Das in 1965 which showed postnatal hippocampal neurogenesis in young rats.
See also
References
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External links
- Media related to Neural stem cells at Wikimedia Commons