Some recent studies show that neural stem cells neural stem cells in the central nervous tissue injury and repair in the treatment of neural functional repairing has broad application prospects, but the neural stem cells to be used clinically are still many questions unanswered.
A nerve sources of stem cells
1.
embryonic tissue embryonic tissue derived from neural stem cell research early and has a more mature technology and methods. It includes all derived from early embryos and stem cells from fetal nervous tissue pluripotent stem cells. study found that from early embryos (morula blastocyst m) of the cells have developmental totipotency (Totipotent), in the right environmental conditions can develop into complete individuals (including the three germ layers in vivo more than 220 types of cells), This early embryonic cells called totipotent cells. Embryonic stem cells can all long-term culture in vitro, and highly undifferentiated nature, under certain conditions or in differentiation and development of fetal neural stem cells in the body, including cells of all types, including . from fetal neural stem cells in nervous tissue has been confirmed by many scholars, the more the early fetal brain the higher rate of neural stem cells, to birth, only periventricular region, there will be a certain proportion of striatum neural stem cells.
Although the source of the nerve from embryonic stem cell research more neural stem cells obtained more easily and number. but only limited animal studies, to obtain early human embryo (blastocyst) and fetal brain tissue is often difficult In addition to technical conditions, source and quantity restrictions, but also to ethics, organization and other issues of immune rejection, which makes the human neural stem cell research, and clinical application is restricted.
2. adult tissue sources
adult source is from adult nerve cells, or adult non-neural tissue for neural stem cells. adult neural tissue-derived neural stem cells from birth to adult brain tissue wide area. whether it is human or different species of animals Although adult neural stem cells have different biological characteristics, but the existence of sites with great consistency. Many studies have found that the subventricular zone in adult animals, striatum, hippocampus dentate gyrus, the presence of spinal cord and other regions have neural stem cells. Vescovi and Uchida analysis by cloning human cells, confirmed the brain can be isolated from the human embryonic neural stem cells. Pagano and Roy in the study found, and the white matter of adult olfactory bulb neural stem cells and their presence precursor cells. from central nervous tissue of adult neural stem cells in the brain and spinal cord although there are widespread, but because of its very few, access difficulties, and in obtaining neural stem cells have caused neurological damage risk, so the feasibility of practical application in clinical very small.
current adult non-neural tissue-derived neural stem cell research reported gradually increased, mainly in the bone marrow, fat, skin and other tissues, in which bone marrow-derived adult neural stem cells research more. The main method is extraction of animal or human bone marrow, isolated from bone marrow stromal cells by inducing differentiation and purification to obtain neural stem cells. marrow derived adult neural stem cells from adequate access to easy, and autologous bone marrow-derived adult neural stem cell transplantation without immune rejection and to avoid the ethical controversial. But bone marrow stromal cells induced to differentiate into neural cells is very difficult to process technology. We carried out research in recent years in rats, rabbits, cats, dogs, monkeys and human bone marrow stromal cells differentiate into neural cells in series research has solved the technical issues related to induction of differentiation, so that bone marrow derived neural stem cells and to the success rate of the proportion of neural stem cells greatly increased.
Second, neural stem cells induced differentiation and proliferation control
Neural stem cell differentiation regulation by the cell internal and external environment a variety of complex factors, the so-called neural stem cells induced into is the appropriate relevant conditions, neural stem cell differentiation and proliferation during induction and regulation and control, so that the specified direction. The following factors may be involved in the differentiation of neural stem cell proliferation control process.
1. The role of cytokine-induced differentiation of some cytokines
to a certain extent, the differentiation of neural stem cells, but there were no What kind of cytokines in vitro induction of the neural stem cells to differentiate into all of the functionality required (purpose) nerve cells; Li et al (2000) reported retinoic acid (Retinoic acid, RA) and nerve growth factor (Nerve growth factor, NGF ) is directed embryonic stem cells (Embryonic stem cell, ESC) to differentiate into neural cells in common cytokine containing RA in the culture medium from embryonic stem cells containing a foreign, in the three germ layers of the embryoid bodies were attached walls of culture, can be efficient and can be repeatedly differentiated neural cells, these cells express neurofilament M and tubulin, a sodium, potassium and other ion channel characteristics; if ESC with RA for 2 to 3 weeks after induction, you can train the ESC into nerve cells, forming a typical electrophysiological responses of nerve impulses and other nerve cells, and cells with a neuron specific cytoskeleton, synaptic vesicle protein. RA although the induction of ESC differentiation of neural stem cells has a very important role in But in the induction of ESC differentiation into neural stem cells differentiate into, not all the functionality required (purpose) nerve cells, it was reported only 10 ~ 30% ESC to differentiate into neurons, and most of the cells to differentiate into astrocytes and less oligodendrocyte; the same time, in the application of RA induction of ESC differentiation into neural stem cells in fashion needs of other cytokines, in addition to those of RA, there are interleukins (including ILm1, ILm7, ILm9, ILm11, etc.), growth factors (such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), glial cell line-derived neurotrophic factor (GDNF), etc.). different kinds of cytokines, the same cytokines different concentrations, and the combination of multiple cytokines on differentiation of neural stem cells are different. in development and differentiation of neural stem cells at different stages of the role of the same cytokines are also different. a number of studies have shown that neural stem cells to differentiate into a strong functional potential of nerve cells by neural stem cells in different stages of development of Induction of differentiation of the best selection of cytokines, or explore the best combinations of cytokines can increase to some extent, the proportion of neural stem cells.
2. gene regulation of neural stem cell differentiation
Although different cytokines in the induction and differentiation of neural stem cells important role, but the neural stem cells as a brain cell precursor cells, alone or certain kinds of cells by adding a factor or cell culture conditions is difficult to change people's willingness to press for the implementation of directional differentiation of the brain function of a particular nerve cell nerve function. To solve the fundamental problem, to consider the level of intervention by the gene. In order to achieve the level of the gene regulation, we must first clear precursor cells differentiate into neural stem cells a major regulatory gene of the type and nature, in particular, must have a clear decision at different stages of development and differentiation of neural stem cells into nerve cells required for functional differentiation of the dominant gene targeting, which need to activate or silence genes. organisms by phenotypic changes are mainly internal, the expression of genes identified. to differentiated cells and progenitor cells, activate cells and quiescent cells, the mutant cells (such as tumor cells) and as between normal cells are differences in gene expression exist. If the cells in these groups were found between closely related to differential expression of those genes may be related to cell populations of these occurred metabolic and functional changes in the complex to provide meaningful information. has been shown that , gene transfer methods can regulate neural stem cells, for example, can be dopamine hydroxylase (TH) gene into neural stem cells through the induction of differentiation, for dopaminergic neurons.
3. signal transduction in neural stem cells Differentiation
studies have shown that, by the NOTCH signaling pathway to regulate neural stem cells. NOTCH originally refers to a specific mutation in Drosophila form after a series of cloned mammals have the same NOTCH Source Molecular In 1998, Li's study found, Notch signaling activation inhibited embryonic stem cell differentiation - when Notch is activated, the stem cells proliferate; When Notch activity was inhibited, the stem cells into the differentiation process, develop into functional cells. < br> As a signal transduction pathway, NOTCH signaling system signaling processes not yet fully understood. now that the Notch receptor is an integrated membrane protein, is a conservative cell surface receptors, ligands surrounding it with expression in cells are activated by direct contact. the signal transduction process began in the NOTCH receptor ligand binding receptor cytoplasmic shedding from the cell membrane to the nucleus transfer signal to the downstream signaling molecules. The pathway signal transduction mainly through protein-protein interaction, transcription factors caused the change, or raise the target transcription factor genes to achieve the control of specific gene transcription. When NOTCH dysfunction, this way, it is possible to signal change by NOTCH precise control of neural stem cells into functional nerve cells and the ratio of the process.
nerve function because the brain is very complex, different types of neurons responsible for the different neural functions, such as cholinergic neurons, peptidergic neurons ,5-HT neurons and catecholaminergic neurons (including dopaminergic neurons, noradrenergic neurons), etc. Although different neuronal structure consistent with the morphological However, the function of the shoulder is different, the different functions of neurons located in specific parts of the brain, through the synthesis of the corresponding neurotransmitter release or media play to their specific neurological functions. Therefore, the present level of research hard to realize neural stem cells induced differentiation. In most cases, obtained with neural stem cells is not the function of a particular neural stem cells.
Third, neural stem cell transplantation and its effect on the central nervous system injury treatment < br> 1. neural stem cell transplantation for treatment of central nervous system injury
neural stem cell transplantation indications for brain or spinal cord injury caused by neurological damage, such as sports or traumatic sensory aphasia, cerebral cortex motor area of damage caused by hemiplegia or Single paralysis, persistent coma, paraplegia caused by spinal cord injury and other.
2. neural stem cells of several common methods
neural stem cell transplantation methods include: ① cell suspensions stereotactic injection; ② collagen matrix package Buried transplantation; ③ biological material (PGA, PLA, etc.) adsorption transplantation; ④ cell suspension input intravenous; ⑤ cell suspension intraventricular injection or lumbar puncture. In these transplantation methods, is usually the first three methods or by CT guided stereotactic neuronavigation system in the fixed-point transplant under the guidelines, the minimum distance between adjacent injection points for the 5mm. After the two methods is the neural stem cells into 107/ml cell suspension, by intravenous drip ventricle and the lumbar puncture or the neural stem cells injected into cerebrospinal fluid suspension, the role of cell migration through the brain or spinal cord injury area to the migration of accumulation.
3. neural stem cell transplantation for treatment of central nervous system injury
possible mechanisms of neural stem cell transplantation central nervous system injury mechanism is not very clear, may be related to the following factors: ① structural repair nerve tissue from injury, so that the damaged neural pathway to re-pass; ② implanted neural stem cells and settled parts of the interaction between nerve tissue and produce some cytokines, such as peptides, neurotrophic factor, interleukin-class, macrophage colony-stimulating factor and stem cell factor, these cytokines not only promote the repair of neurological function, but also can protect the implanted neural stem cell survival, proliferation, and induction of neural stem cells migrate to the damaged site. ③ neural stem cells to endothelial progenitor cells (endothelia progenitor cells, EPCs), and the role of neuronal differentiation, is conducive to the nerve damage, vascular tissue repair, neural stem cells from the blood circulation and cerebrospinal fluid circulation to the damaged brain (spinal cord) regional migration mechanism is unknown, may be related to the blood - brain barrier and cerebrospinal fluid - brain barrier opening and on the induction of certain cytokines.
IV Looking
source of neural stem cells, Induction of differentiation and transplantation for the repair due to trauma caused by the brain of spinal cord dysfunction Despite important progress, but we believe that there are a lot of work for the clinical need to do before, these include : ① solution of neural stem cells induced into and purification; ② Security: To complete the oncogenicity, toxicity and immune experiments; ③ Effectiveness: In the animal experiments to observe the transplanted neural stem cells survived and peripheral nerve cells have synaptic connections, the availability of neurotransmitter synthesis, the electrical activity of nerves and nerve function impairment with or without improvements. In short, although the neural stem cell research just getting started, there remain many challenges, but its clinical application is broad and I believe in the near future neural stem cells for repair of traumatic brain and spinal cord injury will be a major breakthrough.
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