Subventricular zone
Encyclopedia
The subventricular zone (SVZ) is a paired brain
structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition.
)-positive astrocytic processes that are linked to junctional complexes, yet lack cell bodes except for the rare neuronal stomata. While the function of this layer is yet unknown in humans, it has been hypothesized that the astrocytic and ependymal interconnections of Layer I and II may act to regulate neuronal functions, establish metabolic homeostasis
, and/or control neuronal stem cell proliferation
and differentiation during development. Potentially, such characteristics of the layer may act as a remainder of early developmental life or pathway for cellular migration given similarity to a homologous layer in bovine SVZ shown to have migratory cells common only to higher order mammals.
cell bodies that are believed to maintain a subpopulation of astrocytes able to proliferate in vivo and form multipotent neurospheres of self-renewal abilities in vitro. While some oligodendrocytes and ependymal cells have been found within the ribbon, they not only serve an unknown function, they are uncommon by comparison to the population of astrocytes that reside in the layer. The astrocytes present in Layer III can be divided into three populations through electron microscopy, with no unique functions yet recognizable; the first type is a small astrocyte of long, horizontal, tangential projections mostly found in Layer II; the second type is found between Layers II and III as well as within the astrocyte ribbon, characterized by its large size and many organelles; the third type is typically found in the lateral ventricles just above the hippocampus
and is similar in size to the second type but contains few organelles.
. It is identified by a high presence of myelin
in the region.
1. Ciliated Ependymal Cells (Type E): are positioned facing the lumen of the ventricle, and function to circulate the cerebrospinal fluid
.
2. Proliferating Neuroblasts (Type A): express PSA-NCAM, Tuj1, and Hu, and migrate in line order to the Olfactory Bulb
3. Slow Proliferating Cells (Type B): express Nestin
and GFAP
, and function to ensheathe migrating Type A Neuroblasts
4. Actively Proliferating Cells or Transit Amplifying Progenitors (Type C): express Nestin, and form clusters interspaced among chains throughout region
and self-renewing neurons in the adult brain
, serving as such given the interacting cell types and extracellular molecules promoting such cellular proliferation. Along with the subgranular zone
of dentate gyrus
, the subventricular zone serves as a source of neural stem cells in the process of adult neurogenesis
. It harbors the largest population of proliferating cells in the adult brain of rodents, monkeys and humans.
While it has yet to have been studied in-depth in the human brain, the SVZ function in the rodent brain has been, to a certain extent, examined and defined for its abilities. With such research, it has been found that the dual-functioning astrocyte
is the dominant cell in the rodent SVZ; this astrocyte acts as not only a neuronal stem cell, but also as a supporting cell that promotes neurogenesis
through interaction with other cells. This function is also induced by microglia
and endothelial cells that interact cooperatively with neuronal stem cells to promote neurogenesis in vitro, as well as extracellular matrix components such as teneascin-C (helps define boundaries for interaction) and Lewis X (binds growth and signaling factors to neural precursors). The human SVZ is different, however, from the rodent SVZ in two distinct ways; the first is that the astrocytes of humans are not in close juxtaposition to the ependymal layer, rather separated by a layer lacking cell bodies; the second is that the human SVZ lacks chains of migrating neuroblasts seen in rodent SVZ, in turn providing for a lesser number of neuronal cells in the human than the rodent. For this reason, while rodent SVZ proves as a valuable source of information regarding the SVZ and its structure-to-function relationship, the human model will prove significantly different.
In addition, some current theories propose that the SVZ may also serve as a site of proliferation for brain tumor stem cells (BTSCs), which are similar to neural stem cells in their structure and ability to differentiate into neurons, astrocytes, and oligodendrocytes. Studies have confirmed that a small population of BTSCs can not only produce tumors, but they can also maintain it through innate self-renewal and multipotent abilities. While this does not allow for inference that BTSCs arise from neural stem cells, it does raise an interesting question as to the relationship that exists from our own cells to those that can cause so much damage.
, directed neuronal migration, to the previously mentioned tumorigenesis, as well as many others. Below there are summaries of the work of three different lab groups focusing primarily on one aspect of the SVZ; these include the role of SVZ in cell replacement after brain injury, simulation of NSC proliferation, and role in various tumorigenic cancers.
Romankob et al., in an attempt to observe various cause and effect relationships on the SVZ due to potentially hazardous incidence upon the brain, describe the many experiments that were conducted to determine such outcomes. As was determined, the multitude of cells that exist in the SVZ were found to be somewhat vulnerable to their exposure agents, but affected only to the extent by which observations can be made regarding replacement of dead brain cells.
The effects of irradiation
on the SVZ provided for a recognition of the amount or dose of radiation that can be given is determined mostly by the tolerance of the normal cells near the tumor
. As described, the increasing dose of radiation and age led to decrease in three cell types of the SVZ, yet repair capacity of the SVZ was observed given lack of white matter
necrosis
; this stands for the fact that the SVZ was able to gradually replace the neuroglia of the brain. Chemotherapeutics were also tested for there effects on the SVZ, as they are currently used for many diseases yet provide for complications with the central nervous system
. To do so, methotrexate
(MTX) was used alone and in combination with radiation to find that roughly 70% of the total nuclear density of the SVZ had been depleted, yet given loss of neuroblast
cells (progenitor cells), it was remarkable to find that SVZ NSCs would still generate neurospheres similar to subjects that did not receive such treatment. In relation to interruption of blood supply to the brain, cerebral hypoxia
/ischemia
(H/I) was found to also decrease the cell count of the SVZ by 20%, with 50% of neurons in the striatum
and neocortex
being destroyed., but the cell types of the SVZ killed were as non-uniform as the region itself. Upon subsequent testing, it was found that a different portion of each cell was eliminated, yet the medial SVZ cell population remained mostly alive. This may provide for a certain resiliency of such cells, with the uncommitted progenitor cells acting as the proliferating population following ischemia
. Mechanical brain injury also induces cell migration and proliferation, as was observed in rodents, and it may also increase cell number, negating the previously held notion that no new neuronal cells can be generated.
In conclusion, this group was able to determine that cells in the SVZ are able to produce new neurons and glia throughout life, given it does not suffer damage as it is sensitive to any deleterious effects. Therefore, the SVZ can recover itself following mild injury, and potentially provide for replacement cell therapy to other affected regions of the brain.
In an attempt to characterize and analyze the mechanism concerning the proliferation of
neuronal cells within the subventricular zone, Decressac et al. observed the proliferation of
neural precursors in the mouse subventricular zone through injection of the neuropeptide Y
(NPY). NPY is a commonly expressed protein of the central nervous system that has previously
been shown to stimulate proliferation of neuronal cells in the olfactory epithelium
and
hippocampus
. The peptide
’s effects were observed through BrdU labeling and cell phenotyping that provided evidence for the migration of neuroblasts through the rostral migratory stream to the olfactory bulb
(confirming previous experiments) and to the striatum
. Such data supports the author’s hypothesis in that neurogenesis
would be stimulated through introduction of such a
peptide
.
As NPY is a 36 amino acid
peptide
associated with many physiological and pathological
conditions, it has multiple receptors that are broadly expressed in the developing and mature
rodent brain. However, given in vivo
studies performed by this group, the Y1 receptor displayed specifically mediated neuroproliferative effects through the induction of NPY with increased expression in the subventricular zone. Identification of the Y1 receptor also sheds light on the fact that the phenotype of expressed cells from such mitotic events are actually cells that are DCX
+ (neuroblasts that migrate directly to the striatum
) type. Along with the effects of NPY injection on striatal dopamine
, GABA
and glutamate parameters to regulate neurogenesis
in the subventricular zone (previous study), this finding is still under consideration as it could be a secondary modulator of the aforementioned neurotransmitters.
As is necessary for all research, this group conducted its experiments with a broad perspective on the application of their findings, which they claimed could potentially benefit potential candidates for endogenous brain repair through stimulation of the subventricular zone neural stem cell proliferation. This natural molecular regulation of adult neurogenesis would be adjunct with therapies of appropriate molecules such as the tested NPY and Y1 receptor, in addition to pharmacological derivatives, in providing for manageable forms of neurodegenerative disorders of the striatal area.
In an attempt to characterize the role of the subventricular zone in potential tumorigenesis, Quinones-Hinojosa et al. found that brain tumor stem cells (BTSCs) are stem cells that can be isolated from brain tumors by similar assays used for neuronal stem cells. In forming clonal spheres similar to neurospheres of neuronal stem cells, these BTSCs were able to differentiate into neurons, astrocytes and oligodendrocytes in vitro
, yet more importantly capable of initiating tumors at low cell concentrations, providing a self-renewal capacity. It was therefore proposed that a small population of BTSCs with such self-renewal capabilities were maintaining tumors in diseases such as leukemia
and breast cancer
.
Several characterizing factors lead to the proposed idea of neuronal stem cells (NSCs) being the origin for BTSCs, as they share several features. These features are shown in the figure.
This group provides evidence of the SVZ’s apparent role in tumorigenesis as demonstrated by the possession of mitogenic receptors and their response to mitogenic stimulation, specifically type C cells that express the epidermal growth factor receptor
(EGFR), making them highly proliferative and invasive. Additionally, the existence of microglia
and endothelial cells within the SVZ was found to enhance neurogenesis
, as well as providing for some directional migration of neuroblasts from the SVZ.
In following, while the SVZ has not yet been characterized as an exact site of tumorigenesis, it is distinctly possible that such a relationship exists between the NSC generation of the region and the consistently self-renewing cells of primary tumors that give way to secondary tumors once removed or irradiated.
for neuronal stem cells and its potential role in replacement cell therapy for damaged regions of the brain
, the SVZ has proven and will continue to act as an important insight into cell therapy for many traumatic brain injuries. Current research is being conducted with aims of not only understanding the migratory and regulatory pathways of the neuronal stem cells and their progenitors, but also how to induce and potentially direct them in a desired direction.
While such research has not yet provided for any implementation of these findings, the future may hold possible treatments, chemical or otherwise, that will help those in need of brain cell replacement.
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition.
Layer I
The innermost layer (Layer I) contains a single layer (monolayer) of ependymal cells lining the ventricular cavity; these cells possess apical cilia and several basal expansions that may stand in either parallel or perpendicular to the ventricular surface. These expansions may interact intimately with the astrocytic processes that are interconnected with the hypocellular layer (Layer II).Layer II
The secondary layer (Layer II) provides for a hypocellular gap abutting the former and has been shown to contain a network of functionally-correlated Glial Fibrillary Acid Protein (GFAPGlial fibrillary acidic protein
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
)-positive astrocytic processes that are linked to junctional complexes, yet lack cell bodes except for the rare neuronal stomata. While the function of this layer is yet unknown in humans, it has been hypothesized that the astrocytic and ependymal interconnections of Layer I and II may act to regulate neuronal functions, establish metabolic homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
, and/or control neuronal stem cell proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
and differentiation during development. Potentially, such characteristics of the layer may act as a remainder of early developmental life or pathway for cellular migration given similarity to a homologous layer in bovine SVZ shown to have migratory cells common only to higher order mammals.
Layer III
The third layer (Layer III) forms a ribbon of astrocyteAstrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
cell bodies that are believed to maintain a subpopulation of astrocytes able to proliferate in vivo and form multipotent neurospheres of self-renewal abilities in vitro. While some oligodendrocytes and ependymal cells have been found within the ribbon, they not only serve an unknown function, they are uncommon by comparison to the population of astrocytes that reside in the layer. The astrocytes present in Layer III can be divided into three populations through electron microscopy, with no unique functions yet recognizable; the first type is a small astrocyte of long, horizontal, tangential projections mostly found in Layer II; the second type is found between Layers II and III as well as within the astrocyte ribbon, characterized by its large size and many organelles; the third type is typically found in the lateral ventricles just above the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and is similar in size to the second type but contains few organelles.
Layer IV
The fourth and final layer (Layer IV) serves as a transition zone between Layer III with its ribbon of astrocytes and the brain parenchymaParenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...
. It is identified by a high presence of myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
in the region.
Cell types
Four cell types are described in the SVZ:1. Ciliated Ependymal Cells (Type E): are positioned facing the lumen of the ventricle, and function to circulate the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
.
2. Proliferating Neuroblasts (Type A): express PSA-NCAM, Tuj1, and Hu, and migrate in line order to the Olfactory Bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
3. Slow Proliferating Cells (Type B): express Nestin
Nestin (protein)
Nestin is a type VI intermediate filament protein. These intermediate filament proteins are expressed mostly in nerve cells where they are implicated in the radial growth of the axon...
and GFAP
Glial fibrillary acidic protein
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
, and function to ensheathe migrating Type A Neuroblasts
4. Actively Proliferating Cells or Transit Amplifying Progenitors (Type C): express Nestin, and form clusters interspaced among chains throughout region
Function
The SVZ is a known site of neurogenesisNeurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
and self-renewing neurons in the adult brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, serving as such given the interacting cell types and extracellular molecules promoting such cellular proliferation. Along with the subgranular zone
Subgranular zone
The subgranular zone is a brain region in the hippocampus where adult neurogenesis occurs. It is one of the two major sites of adult neurogenesis in the brain, along with the subventricular zone .- Structure :...
of dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
, the subventricular zone serves as a source of neural stem cells in the process of adult neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
. It harbors the largest population of proliferating cells in the adult brain of rodents, monkeys and humans.
While it has yet to have been studied in-depth in the human brain, the SVZ function in the rodent brain has been, to a certain extent, examined and defined for its abilities. With such research, it has been found that the dual-functioning astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
is the dominant cell in the rodent SVZ; this astrocyte acts as not only a neuronal stem cell, but also as a supporting cell that promotes neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
through interaction with other cells. This function is also induced by microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
and endothelial cells that interact cooperatively with neuronal stem cells to promote neurogenesis in vitro, as well as extracellular matrix components such as teneascin-C (helps define boundaries for interaction) and Lewis X (binds growth and signaling factors to neural precursors). The human SVZ is different, however, from the rodent SVZ in two distinct ways; the first is that the astrocytes of humans are not in close juxtaposition to the ependymal layer, rather separated by a layer lacking cell bodies; the second is that the human SVZ lacks chains of migrating neuroblasts seen in rodent SVZ, in turn providing for a lesser number of neuronal cells in the human than the rodent. For this reason, while rodent SVZ proves as a valuable source of information regarding the SVZ and its structure-to-function relationship, the human model will prove significantly different.
In addition, some current theories propose that the SVZ may also serve as a site of proliferation for brain tumor stem cells (BTSCs), which are similar to neural stem cells in their structure and ability to differentiate into neurons, astrocytes, and oligodendrocytes. Studies have confirmed that a small population of BTSCs can not only produce tumors, but they can also maintain it through innate self-renewal and multipotent abilities. While this does not allow for inference that BTSCs arise from neural stem cells, it does raise an interesting question as to the relationship that exists from our own cells to those that can cause so much damage.
Current research
There are currently many different aspects of the SVZ being researched by individuals in the public and private sectors. Such research interests range from the role of the SVZ in neurogenesisNeurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
, directed neuronal migration, to the previously mentioned tumorigenesis, as well as many others. Below there are summaries of the work of three different lab groups focusing primarily on one aspect of the SVZ; these include the role of SVZ in cell replacement after brain injury, simulation of NSC proliferation, and role in various tumorigenic cancers.
Roles of the mammalian subventricular zone in cell replacement after brain injury
Michael J. Romankob, Radoslaw Rolac, John R. Fikec,d, Francis G. Szele, Maria L.V. Dizone, Ryan J. Fellingb, Christine Y. Brazelf, Steven W. Levisona,b,*. (2004). Progress in Neurobiology (74). 77-99.Romankob et al., in an attempt to observe various cause and effect relationships on the SVZ due to potentially hazardous incidence upon the brain, describe the many experiments that were conducted to determine such outcomes. As was determined, the multitude of cells that exist in the SVZ were found to be somewhat vulnerable to their exposure agents, but affected only to the extent by which observations can be made regarding replacement of dead brain cells.
The effects of irradiation
Irradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
on the SVZ provided for a recognition of the amount or dose of radiation that can be given is determined mostly by the tolerance of the normal cells near the tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. As described, the increasing dose of radiation and age led to decrease in three cell types of the SVZ, yet repair capacity of the SVZ was observed given lack of white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
; this stands for the fact that the SVZ was able to gradually replace the neuroglia of the brain. Chemotherapeutics were also tested for there effects on the SVZ, as they are currently used for many diseases yet provide for complications with the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. To do so, methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
(MTX) was used alone and in combination with radiation to find that roughly 70% of the total nuclear density of the SVZ had been depleted, yet given loss of neuroblast
Neuroblast
A neuroblast is a dividing cell that will develop into neurons or glia. The characterisation of neuroblasts and their development in Drosophila melanogaster was widely achieved by Chris Doe, Corey Goodman and Mike Bate. In humans, neuroblasts produced by stem cells in the adult subventricular zone...
cells (progenitor cells), it was remarkable to find that SVZ NSCs would still generate neurospheres similar to subjects that did not receive such treatment. In relation to interruption of blood supply to the brain, cerebral hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
/ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
(H/I) was found to also decrease the cell count of the SVZ by 20%, with 50% of neurons in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
and neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
being destroyed., but the cell types of the SVZ killed were as non-uniform as the region itself. Upon subsequent testing, it was found that a different portion of each cell was eliminated, yet the medial SVZ cell population remained mostly alive. This may provide for a certain resiliency of such cells, with the uncommitted progenitor cells acting as the proliferating population following ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
. Mechanical brain injury also induces cell migration and proliferation, as was observed in rodents, and it may also increase cell number, negating the previously held notion that no new neuronal cells can be generated.
In conclusion, this group was able to determine that cells in the SVZ are able to produce new neurons and glia throughout life, given it does not suffer damage as it is sensitive to any deleterious effects. Therefore, the SVZ can recover itself following mild injury, and potentially provide for replacement cell therapy to other affected regions of the brain.
Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice
Decressac, M., Prestoz, L., Veran, J., Cantereau, A., Jaber, M., & Gaillard, A. (2009).Neurobiology of Disease, 34(3), 441-449.In an attempt to characterize and analyze the mechanism concerning the proliferation of
neuronal cells within the subventricular zone, Decressac et al. observed the proliferation of
neural precursors in the mouse subventricular zone through injection of the neuropeptide Y
Neuropeptide Y
Neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system."NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy." The main effect is increased food...
(NPY). NPY is a commonly expressed protein of the central nervous system that has previously
been shown to stimulate proliferation of neuronal cells in the olfactory epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
and
hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. The peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
’s effects were observed through BrdU labeling and cell phenotyping that provided evidence for the migration of neuroblasts through the rostral migratory stream to the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
(confirming previous experiments) and to the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. Such data supports the author’s hypothesis in that neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
would be stimulated through introduction of such a
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
.
As NPY is a 36 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
associated with many physiological and pathological
conditions, it has multiple receptors that are broadly expressed in the developing and mature
rodent brain. However, given in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
studies performed by this group, the Y1 receptor displayed specifically mediated neuroproliferative effects through the induction of NPY with increased expression in the subventricular zone. Identification of the Y1 receptor also sheds light on the fact that the phenotype of expressed cells from such mitotic events are actually cells that are DCX
Doublecortin
Doublecortex; lissencephaly, X-linked , also known as DCX, is a gene.Doublecortin is a microtubule-associated protein expressed by neuronal precursor cells and immature neurons in embryonic and adult cortical structures...
+ (neuroblasts that migrate directly to the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
) type. Along with the effects of NPY injection on striatal dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and glutamate parameters to regulate neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
in the subventricular zone (previous study), this finding is still under consideration as it could be a secondary modulator of the aforementioned neurotransmitters.
As is necessary for all research, this group conducted its experiments with a broad perspective on the application of their findings, which they claimed could potentially benefit potential candidates for endogenous brain repair through stimulation of the subventricular zone neural stem cell proliferation. This natural molecular regulation of adult neurogenesis would be adjunct with therapies of appropriate molecules such as the tested NPY and Y1 receptor, in addition to pharmacological derivatives, in providing for manageable forms of neurodegenerative disorders of the striatal area.
The human subventricular zone: A source of new cells and a potential source of brain tumors
Alfredo Quiñones-Hinojosa, Kaisorn ChaichanaIn an attempt to characterize the role of the subventricular zone in potential tumorigenesis, Quinones-Hinojosa et al. found that brain tumor stem cells (BTSCs) are stem cells that can be isolated from brain tumors by similar assays used for neuronal stem cells. In forming clonal spheres similar to neurospheres of neuronal stem cells, these BTSCs were able to differentiate into neurons, astrocytes and oligodendrocytes in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, yet more importantly capable of initiating tumors at low cell concentrations, providing a self-renewal capacity. It was therefore proposed that a small population of BTSCs with such self-renewal capabilities were maintaining tumors in diseases such as leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
.
Several characterizing factors lead to the proposed idea of neuronal stem cells (NSCs) being the origin for BTSCs, as they share several features. These features are shown in the figure.
This group provides evidence of the SVZ’s apparent role in tumorigenesis as demonstrated by the possession of mitogenic receptors and their response to mitogenic stimulation, specifically type C cells that express the epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR), making them highly proliferative and invasive. Additionally, the existence of microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
and endothelial cells within the SVZ was found to enhance neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
, as well as providing for some directional migration of neuroblasts from the SVZ.
In following, while the SVZ has not yet been characterized as an exact site of tumorigenesis, it is distinctly possible that such a relationship exists between the NSC generation of the region and the consistently self-renewing cells of primary tumors that give way to secondary tumors once removed or irradiated.
Medical applications
Given the understanding of the SVZ as a region of neurogenesisNeurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
for neuronal stem cells and its potential role in replacement cell therapy for damaged regions of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, the SVZ has proven and will continue to act as an important insight into cell therapy for many traumatic brain injuries. Current research is being conducted with aims of not only understanding the migratory and regulatory pathways of the neuronal stem cells and their progenitors, but also how to induce and potentially direct them in a desired direction.
While such research has not yet provided for any implementation of these findings, the future may hold possible treatments, chemical or otherwise, that will help those in need of brain cell replacement.