Recent research communications indicate that the adult human brain is capable of producing stem cells which contains undifferentiated and multipotent precursor cells (Westerlund et al., 2003). The insight that stem cells might be central to brain plasticity, including but not limited to adult neurogenesis, is only a recent idea.
Adult neurogenesis is the production of new, functional neurons in the adult brain (Kemp2011). It is a complex process rather that an single event. If there are new neurons developed in adult brain, that means neurogenic region is capable of provide stem cells. Recent studies proved that the hippocampus and olfactory bulb are the neurogenic regions in human brain( ). So far it has been clearly proved in such areas: in the subventricular zone of the lateral ventricles( ), olfactory bulb, subgranular zone of the dentate gyrus in the hippocampus (Ratajczak2011). Current studies suggest that stem cells probably make new neurons in another part of the human brain and also other additional locations( ). But overall, only a few experiments in the human brain has been done and they are insufficient to draw some conclusions about the potential of plasticity in the human brain
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This essay will review how the stem cells in the adult brain are generated and their functional properties of the new neurons with current experiments and findings to support the idea. It is clear, over the decade, the increasing number of publications on adult neurogenesis is impressive and reveals how much the scientific community is excited and attracted to more and more researches (Kemp 2011).
Although the recent findings were surprising, hints had actually appeared many decades ago. Joseph Altman in 1965 reported that the neuronal production in the hippocampus (an area important to memory and learning) of adult rats , more precisely "dentate gyrus" ( ). His early reports raised the idea of precursor cells' giving rise to the neurons and the human brain has some regenerative potential. This concept was not viewed until recently because at that time there was no direct experimental evidence to support this assumption (altmen1965; Kaplan 1983).
Historically it was believed that once embryonic development has ceased, stem cells are unable to regenerate after recovery except in bone marrow, skin, and the intestines (Ramon y Cajal 1928). Thus, the scientists believed "no new neuron" theory that the adult human brain was incapable of generating new nerve cells. However, rediscovery of the neural stem cells in the late 1990's, opened a new chapter of neurobiology history and solved the question of the origin of adult neurogenesis. In 1998, Eriksson's pivotal study demonstrated neurogenesis in the adult human hippocampus by using bromide-oxyuridine(BrdU) DNA marker. He proved stem cells' proliferation and differentiation, more strictly saying they all displayed granule cells in the dentate gyrus during the patients' adulthood (Kemp, eirkkson). In the following year, Johansson obtained adult hippocampal and lateral wall tissues from epilepsy patients and found new neurospheres formed in culture which contained multipotent self-renewing stem cells (Erikkson1998;Johansson 1999).
Erikkson's confirmation of existing neural stem cells in the adult brain ( ) stimulated the scientific community and became scientifically interesting. Many current studies are making progress to this newly concept of adult neurogenesis and slowly getting answers from opened questions raised for many decades.
Firstly, to understand some fundamental principles underlying adult neurogenesis it is essential to know what is actually meant by stem cells. Stem cells can be fall in two major different degrees in the brain: firstly, ability to undergo unlimited self-renewal, secondly ability to generate a variety of differentiated cells "multipotency" ( ).
In early neural development, neuroepithelial cells (neural stem cells) present when the nervous system is forming which exposed to various signals such as sonic hedgehog and fibroblast growth factors. When neurogenesis starts, stem cells are transformed to radial glial cells and the complexity of their microenvironment increases due to the emergence of various types of neuronal progenitors (Kazanis) , differentiated cells and extracellular signaling molecules. Finally, during adulthood, neural stem cells assume astroglial morphology and reside in specific microenvironments that are called neurogenic niches (Kazanis). Neurons and glia are continuously generated under the control of mechanisms largely similar to embryonic development period.
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A brain area that can generate neurons is called "neurogenic" region. Based on the present stage of knowledge, two known neurogenic regions have been confirmed in the adult human brain, the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and subventricular zone (SVZ) of the lateral walls of the lateral ventricles ( ). The scientists are continuously investigating to locate the origin of new neurons in the human brain but for various safety reasons, it is extremely difficult to monitor new neurons in a living person. Thus, for the safety reasons, most cases have been studied in rodents brain.
New studies have shown that in the neurogenic regions, morphologivally characteristic radial glial cell persists into adult mammals adulthood (Kriegstein, namda). Radial glia cells act as a precursor cell in the developing brain (primary progenitors or neural stem cells, NSCs) and serves as a guidance structure for the migration of newly generated neurons to their appropriate position in the cortex.(namda, kriegstein, kempermann)
Neural stem cells in the adult hippocampus
Although we speak of neurogenesis in the hippocampus, neurogenesis actually takes place only in one subregion, the dentate gyrus, not any other sub-areas, more strictly speaking it is between the dentate gyrus and CA3. Within this region, the axons of the new granule cells add to the mossy fiber connection. In the human hippocampus granule cell development starts from totipotent stem cell, which is able to give rise to unspecialized stem cells committed to producing cells of the brain. These committed cells later produce progenitor cells destined to make only neurons or only glial cells (which promote neuronal survival). Ultimately, neuronal progenitors induce granule cells in the hippocampus or other kinds of neurons elsewhere in the brain. The cycle repeats throughout life in the human hippocampus.
Eriksson's earlier study provided principle that new neurons were indeed formed in the adult human brain but also showed that the new neurons could be detected a long time after BrdU was injected. However, the study did not reveal the total number of newly born neurons in the hippocampus in the adult brain, nor how this number changed with age. In 2004, Jin et al. used Western blotting and immunohistochemistry studies to determine the level of neurogenic markers in the hippocampus, where the brain tissue prepared from normal and Alzheimer's disease-affected brains. This study reported increases in the amount of proneurogenic proteins in Alzheimer's disease tissue.
Neural stem cells in the adult olfactory bulb
The stem cells that yield new neurons in the olfactory system line the lateral wall of lateral ventricle. Studies demonstrated that certain descendants of these stem cells mighrate a good distance into the olfactory bulb, where they take on the characteristic features of neurons in that area. In the adult brain, rodent and human studies reveal that neurogenesis continues in the subventricular zone (SVZ) throughout adult life. (altman, Eriksson, Curtis). The SVZ contains B cells, quiescent NSCs, frequently referred to as SVZ astrocytes give rise to actively proliferating C cells that function as Intermediate progenitor cells (IPCs) or transit amplifying progenitors in the adult brain. Type C cells give rise to immature neuroblasts (A cells), which migrate in chains to the olfactory bulb, where they differentiate into interneurons.
Other than previously mentioned regions is condisdered as non-neurogenic regions. Studies have been taken in rodents, piriform cortex, reports on olfactory tubercle ( ), amygdala ( ), hypothalamus ( ) but shows very controversial evidence, so that adult neurogenesis in theses regions cannot be taken as proven at the present time. In the neocortex, good suggestive evidence ofr very low levels of adult neurogenesis extist, especially in Layer VI and after ischemia, but the description is not complete yet and several controversial issues remain. Other studies reported neurogenesis in the neocortex of adult primates (Gould 2001) but was not confirmed by other laboratories (Kemperman)
Function/ Do the new neurons work?
Most people intuitively assume that new neurons in the adult brain are beneficial and might provide a means to actively improve brain function and cognition. It is very important that the new neural cells are functional! "Specific function is the key to the relevance of adult neurogenesis"(Kemp). Also functional relevance of the new neurons is crucial to clinical relevance of regenerative neurogenesis.
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Precursor cells from the adult neurogenic regions generated appropriate functional neuronal phenotypes in vitro, demonstrated by electrophysiolocal measurements (Songâ€¦2077,2002). The same applies to the olfactory bulb, but due to the more complex lineage relationships (), and the greater variety of interneurons, the result is not as homogenous.
Regulating Factors/ what generates the new neurons?
New findings have now confirmed that different culture conditions can determine the properties of precursor cells and even induce "stemness", with different sets of culture conditions yielding incommensurable results (). In 2000, Theo D. Plamer applied the niche concept of stem cell biology to adult neurogenesis and linked the process of adult neurogenesis to the vasculature within that niche. The key role of FGF2 in releasing the stemness properties of cells in the adult brain is one key example (Palmer).
In a review of the subject, other study has stressed the surprising oberservation that cell-cell interactions in the neurogenic niches of the adult brain have much in common with the niche-like environment of a synapse. The potential of Pax6 to convert bona fide astrocytes into neuronal progenitor cells, applies in particular to the role of astrocytes in the niche. This means that properties of neural precursor cells can be changed by external cues. In any cases, there seem to be differences in sensitivity of various cell types to particular sets of environmental cues or genetic manipulation.
In the hippocampal neurogenesis, exercise and an enriched environment have been shown to promote the survival of neurons and the successful integration of newborn cells into the existing hippocampus. Another factor is central nervous system injury since neurogenesis occurs after cerebral ischemia, epileptic seizures, and bacterial meningitis. ( ) on ther other hand, conditions such as chronic stress and aging can result in a decreased neuronal proliferation.
Over recent years it has been clear that neurogenesis is not only influenced by a variety of clinically relevant factors, such as stress, ageing, neurodegenerative disorders, stroke, epilepsy, etc. but links have also been established that relate disturbances of neurogenesis to depression and cognitive deficits. Often it remains undecided whether influence actually reflects a direct effect.
Research data draws that the absolute number of new cells is low relative to the total number in the brain but the discovery of the neural stem cells raised some tantalizing prospects for medicine and new excitements for scientific communit (Kempermann and Gage1999)
With the confirmation that such adult neural stem cells were generating new neurons within the adult human brain, stem cell-based regenerative therapies or brain repair to replace cellular losses appeared to be suddenly nearer. But progress made over recent years notwithstanding, it is clear that a deeper understanding of audlt neurogenesis is prerequiste to achieving these goals in the advance of medical practice.
Although the purpose of human neurogenesis being hotly debated, several research groups have focused on the effect of neurodegenerative diseases in the brain to determine the strength of the endogenous regenerative response. (Curtis 2011; Ratajczk 2011). There are several clinical situations where stem cells could be employed to recover proper function of CNS. The most important are stroke, traumatic brain injury, spinal cord injury and neurodegenerative disorders (Alzheimer's disease, Parkinsonism, amyotrophic lateral sclerosis and Huntington's disease) ( ).
Why and How theses new neurons or neuronal stem cells can regenerate the disease? Show any experiments or results to back up the fact.
Human embryonic stem cells hold great promise in regenerative medicine due to their ability to become any kind of cell needed to repair and restore damaged tissues. But the potential of hESCs has been constrained by a number of practical problems, not least among them the difficulty of growing sufficient quantities of stable, usable cells and the risk that some of these cells might form tumors.
To produce the neural stem cells, Zhang, with co-senior author Sheng Ding, PhD, a former professor of chemistry at The Scripps Research Institute and now at the Gladstone Institutes, and colleagues added small molecules in a chemically defined culture condition that induces hESCs to become primitive neural precursor cells, but then halts the further differentiation process."And because it doesn't use any gene transfer technologies or exogenous cell products, there's minimal risk of introducing mutations or outside contamination," Zhang said. Assays of these neural precursor cells found no evidence of tumor formation when introduced into laboratory mice.
By adding other chemicals, the scientists are able to then direct the precursor cells to differentiate into different types of mature neurons, "which means you can explore potential clinical applications for a wide range of neurodegenerative diseases," said Zhang. "You can generate neurons for specific conditions like amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Parkinson's disease or, in the case of my particular research area, eye-specific neurons that are lost in macular degeneration, retinitis pigmentosa or glaucoma."
Researchers in Germany have produced an antibody that allows them to distinguish the numerous types of stem cells in the nervous system better than before.
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"In order to use stem cells for therapeutic purposes, it is important to be able to distinguish between the different types", explained Eva Hennen of the RUB Department of Cell Morphology and Molecular Neurobiology (Faculty of Biology and Biotechnology).
The antibody 5750 recognises a specific sugar residue on the cell surface, which is called LewisX. The research group lead by Prof. Dr. Andreas Faissner has now been able to use LewisX for the first time to separate different types of stem cells. The researchers report on their results in the Journal of Biological Chemistry.
Unexpected sugar diversity
Antibodies that recognise the LewisX sugar residue are used routinely to identify so-called neural stem cells from which the various cells of the nervous system originate. Prof. Faissner's team has now shown that the designation "LewisX" does not just cover a single sugar motif, but a whole range of different sugar residues. Different types of neural stem cells are equipped with individual combinations of LewisX sugar residues on their cell surface. The new Bochum antibody 5750 recognises a different LewisX sugar residue to the antibodies previously used. "This sugar diversity could also be interesting for cancer diagnosis" Prof. Faissner explained, "because LewisX sugars have also been detected on tumour cells".
Identifying properties of stem cells
With the aid of the new antibody 5750, certain types of neural stem cells can be isolated from a mixture of different cell types. The aim of Prof. Faissner's research group is now to examine the properties of the stem cells which carry the LewisX sugar residues. The researchers have already found out that the LewisX motif on the cell surface changes when the stem cells develop further - for example into oligodendrocytes, which form the insulation layer of the nerve cells, or into nerve cells themselves.
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"Researchers can compare the genes active in brain regions that display neurogenesis and in brian regions that do not. Genetic studies are under way. If the genes participating in neuronal generation can be identified, investigators should be able to discover their protein products and to tease out the precise contributions of the genes and their proteins to neurogenesis." (Kemperman and Gage)
Although most of the human studies have focused on the hippocampus, there is a groundswell of evidence that there is greater plasticity in the subventricular zone and in the ventriculo-olfactory neurogenic system (Curtis 2011)
By the year 2011, adult neurogenesis had become generally accepted as a phenomenon, but with respect to some key issues the field still had mkore questions than anwers. Most important, the question of what the new neurons are good for had barely been touched. As discussed previously, we today have a fairly good idea of how and why new neurons might be beneficial for the brain.(Kemp. pg44)
However to understand the functional relevance of neurogenesis modulation an its potential role in the aetiology of neurolocial disorders, it is necessary to be able to assess and monitor neurogenesis in vivo in a fashion that is minimally invasive. It is essential to have means to assess the localization, intergration and survival of new neurons, and to ensure that no tumour forms from uncontrolled cell proliferation.
Various imaging techniques are available for the detection of neurogenesis. From a clinical perspective, the development of imagin producers based on the use of currently available equipemtn, ie RMI and PET scanners, would be amajor advantage for their rapid and widespread deployment.(Despres) future Imaging methods hopefully allow us to identify neural stem cells and neuronal precursors. The major challenge to overcome in respect to in vivo imaging of neurogenesis remains the improvement of the specificity of detection for neurogenesis without invasive.
Adult neural stem cells don't seem to exist for the purpose of replacing damaged neurons, but we believe that by identifying and learning to manipulate the signals that control their proliferation and differentiation we can use them for that purpose," Schaffer says.
Toward this end he and his colleagues have taken both theoretical and computational approaches to unmasking the regulatory elements in adult neural stem cells. In their modeling work, they focused their investigations on a few prime suspects, such as the Sonic hedgehog protein. This soluble signaling protein was known to play a critical role in controlling the proliferation of numerous mammalian cell populations during early development, but little was known about its role in the adult stage.
To determine the role of the Sonic hedgehog protein in adult mammals, Schaffer and his colleagues harvested neural stem cells from rats, then cultured these cells with Sonic hedgehog protein. Their success in boosting the proliferation of neural stem cells in vitro led to in vivo experiments with adult rats.
The Sonic hedgehog gene was delivered to the hippocampus of each experimental animal through a special virus, called an adeno-associated viral vector. This genetic engineering resulted in the observed tripling of neural stem cells. In addition, injecting cyclopamine, a known pharmacological inhibitor of the Sonic hedgehog gene, significantly reduced neural stem cell proliferation in test rats.
"The next step is to identify signaling proteins that regulate differentiation in neural stem cells," says Schaffer. "We'd also like to know more about the mechanism by which the Sonic hedgehog network of proteins is regulating stem cell proliferation. Cells are exposed to a lot of different regulatory signals, which they must correctly interpret to carry out functional decisions. We'd like to know more about how this information processing system works."
A major challenge to the potential therapeutic value of adult stem cells has been that these cells exist in small numbers that only decrease with age. Discovering cell fate switches that can substantially boost neural stem cell populations represents a big step forward. However, Schaffer is quick to caution that it may be another 10 to 20 years before adult neural stem cells play any significant role in therapy.
"With these neural stem cells, I think we're now at the stage that research with monoclonal antibodies was in the 1980s," he says. "However, if we continue to make progress, the potential implications for medical research are enormous."
Collaborating with Schaffer on this research were Karen Lai and Matthew Robertson, who are both with UCB's Chemical Engineering Department and the Helen Wills Neuroscience Institute.REFERENCES
Westerlund, U., Moe, M. C., Varghese, M., Berg-Johnsen, J., Ohlsson, M., Langmoen, I. A., et al. (2003). Stem cells from the adult human brain develop into functional neurons in culture. Exp Cell Res, 289(2), 378-383.