Endogenous Neural stem Cells and Neurological Disorders

NSCs are multipotent in nature which produces glia and neural cells in human brain. In vitro study shows that Induced pluripotent stem cells (iPSCs) and embryonic Stem cells (ESCs) are capable to produce NSCs [1-5] in animal studies exogenous NSCs transplantation for neurological disorders shows good result which produced from ESC or iPSCs [6-11] these transplanted Exogenous ESC shows immunological response in recipient. in animal study model, few Study shows that ESCs formed tumour in rodents [10-16] in human risk of tumour formation must be evaluated [17]. Space occupying tumour is fatal due to limited space of intracranial cavity. Researchers show that new neurons can be generated from fibroblast cells by Trans differentiation which avoid risk of tumour formation [18].


Introduction
NSCs are multipotent in nature which produces glia and neural cells in human brain. In vitro study shows that Induced pluripotent stem cells (iPSCs) and embryonic Stem cells (ESCs) are capable to produce NSCs [1][2][3][4][5] in animal studies exogenous NSCs transplantation for neurological disorders shows good result which produced from ESC or iPSCs [6][7][8][9][10][11] these transplanted Exogenous ESC shows immunological response in recipient. in animal study model, few Study shows that ESCs formed tumour in rodents [10][11][12][13][14][15][16] in human risk of tumour formation must be evaluated [17]. Space occupying tumour is fatal due to limited space of intracranial cavity. Researchers show that new neurons can be generated from fibroblast cells by Trans differentiation which avoid risk of tumour formation [18].
It was find out that NSCs (Sub ventricular zone of lateral ventricles and Sub granular zone of dentate gyrus) produce new neurons And Glia in human brain in Adult [19][20][21][22][23][24][25][26] if there is trauma or pathological insult to brain then NSCs are stimulated to regenerate glia and new neurons [27,28]. Using endogenous NSCs as treatment for neurological disorders is best option because it avoids ethical issues and immunological responses also there is no chance of tumour formation.

Adult brain and endogenous NSCs
Endogenous NSCs generate neurons continuously in SVZ and SGZ In the adult brain unfortunately Phenotypically there is no specific marker protein for adult NSCs [29,30], NSCs express electrophysiological and morphological characteristics of astrocytes; express GFAP (glial fibrillary acidic protein) which is marker of Astrocytes.

The NSCs in the SGZ
Learning, memory, emotion, mood are monitored and regulated by hippocampus which is important part of limbic system. Through dentate gyrus, neuronal input passes from neocortex to the hippocampal circuitry.

Process of new neuron generation in the Olfactory Bulb
Chain of new neurons ultimately reach to olfactory bulb where new neurons detach themselves from chain and migrate to granule cell layer(GCL) and glomerular layer(GL),at last they differentiate into granule cells, periglomerular cells ,olfactory interneurons by the help of tenascin-R and glycoprotein Reelin [87,88]. Some of these neurons are remains longer than year [89,90]. Newly added Interneurons are involved in odour discrimination but their actual function is unclear in the olfactory circuit [91,92].

Regeneration of neurons by endogenous NSCs
Trauma, stroke, neurodegenerative diseases are pathological insult in which NSCs proliferation increases and newly formed neurons appeared at damaged area. Recent study on human post mortem brain revealed that new neurons produce after insult in cerebral infarction patients [93][94][95] these findings shows that neuronal regeneration in mammalian brain is possible, but spontaneous regeneration of neuron should not compensate loss of neurons. In adult gerbil model and rat model of insult-induced neurogenesis studies showed that globalischemia causes death of pyramidal neurons in the CA 1 region of hippocampus activate proliferation of NSCs in SGZ region and increases number of new granule neurons in the GCL [96,97]. In ischemic stroke model, induced by middle cerebral artery occlusion (MCAO), small striatal projection neurons regenerated [98,99]. SVZ is the potential reservoir of NSCs, these neurons forms new progeny with strong migratory capacity and which can be compensate loss neuron in pathological conditions of brain .SVZ need to be target to restore and replenish lost function by producing new neurons.
Alterations in the microenvironment play important role in NSCs activation after insult to brain in ischemic stroke due to sudden onset, causes immune responses immediate after lesion, in which microglia and astrocytes activate surrounding infarcted area with T-lymphocytes infiltration into the damaged brain [100][101][102] these cells produce growth factors and cytokines which affect neurogenic function of NSCs [103,104]. NSCs proliferation stimulate by growth factors and cytokines in the SVZ [59, 105,106] angiogenesis is important to activate NSCs after stroke, study shows that vasculature is important component of stem cell niche which activate proliferation of NSCs [53, 107,108].
Formed new neurons formed chain and migrate towards damaged area [99,109] vascular endothelial cells produced stromal derived factor 1(SDF1) and angiopoietin 1(Ang1) which control migration of new neurons and also controlled by monocyte chemo attractant protein 1 (MCP1) which expressed by activated astrocytes and microglia in the damaged area [109][110][111][112][113] the receptors of signals of these molecules like CXCR4, Tie2, CCR2 respectively expressed on migrating new neurons. Hence interaction of glia and vasculature regulate migration of new neurons in the injured brain.
SVZ derived GFP labelled cells possess long processes ,express NeuN and form synaptic structures in the damaged striatum 90 days after ischemia induction under electron Open Access Journal of Neurology & Neurosurgery microscope [99] gliogenic proliferation of NSCs occurs more after insult than neurogenic [114] migrating new neurons die before differentiating into mature neurons in the damaged area [98]. NSCs don't shows neurogenic differentiation in SVZ [115,116]. Apparently there are limitations of regeneration of damaged brain tissue by activating endogenous NSCs, some of studies shows beneficial effect in which neurogenesis promoted such as treatment with erythropoietin, statins, activated protein C,HDAC inhibitors and EGF/FGF-2 [117,[119][120][121][122][123][124].

Regeneration of myelin by endogenous NSCs
Myelin sheath covers axons and nerve conduction is important function of it which carries electrical impulses. Oligodendrocyte form myelin sheath in central nervous system. In multiple sclerosis demyelination occurred. Demyelination impairs nerve impulse conduction, causes variety of neurological impairments. NG 2 chondroitin sulphate expressing endogenous oligodendrocyte progenitor cells regenerate oligodendrocyte [125,126]. NSCs in SVZ are also involve in regeneration of oligodendrocyte, recent study shows it [127][128][129].
Demyelination is the process in which regeneration of myelin sheath is required to restore normal function, in these conditions spontaneous regeneration of myelin will not completely recover injury. Allotransplantation of exogenous cells shows myelination in animal model of demyelination. For successful neuronal regeneration, the appropriate regeneration of oligodendrocyte is also needed Conclusion SVZ is the store house of NSCs which produce new neurons that ultimately travel to damaged part of brain and regenerate damaged tissue of brain .NSCs differentiate into mature neurons and in oligodendrocyte which contribute to Remyelination. It was observed in traumatic injury or in hypoxic condition to brain tissue that NSCs in SVZ proliferate and regenerate intermediate new neuron which transforms into mature neuronal cells; these mature neuronal cells travel to injured site and contribute to restore function of that damaged part. Using of exogenous NSCs induced from ESCs or iPSCs are facing ethical problem, shows immunological responses in recipient and having ability of tumour formation. Application of endogenous NSCs needs to be evaluated on the basis of molecular study in preclinical animal model. Need to be evaluating exact molecular mechanism which control endogenous NSC and their progeny in near future. Selfrepair strategy governed by Endogenous NSC is needed to be established for clinical application in brain tissue damage.