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- Electrical Stimulation Elicits Neural Stem Cells Activation: New Perspectives in CNS Repair.
In the future, ES combined with stem cell therapy or other cues probably becomes an approach for promoting brain repair. Electrical stimulation ES is a kind of modern treatment method, such as electroconvulsive therapy Sackeim et al. Not only in preclinical but also in clinical studies, ES is widely proposed for use in many neurological and psychiatric disorders. However, the underlying therapeutic mechanisms remain greatly uninvestigated. Research into relation between ES and specific disorders suggests that functional recovery is attributed to following mechanisms, by means of alterations of cortical excitability Ludemann-Podubecka et al.
Neural plasticity mainly includes synapse formation, dendritic structure, and neurogenesis Lendvai et al. Neural stem cells NSCs are self-renewing and multipotent cells that can give rise to neurons, astrocytes, and oligodendrocytes. They exist in the subventricular zone SVZ of the lateral ventricle and the dentate gyrus subgranular zone SGZ of the hippocampus throughout life Reynolds and Weiss, ; Alvarez-Buylla and Lim, On the other hand, it has been reported that somatic cells, such as fibroblasts and astrocytes, have been reprogramed into induced NSCs with specific transcription factors Ganat et al.
NSCs in the central nervous system CNS can be activated by various physiological and pathological stimuli, indicating that endogenous NSCs can be a potential therapy for brain tissue repair. In addition, the transplantation of exogenous NSCs has been verified feasible in a broad range of animal disease models Tang et al. As they are transplanted or intrinsically activated, NSCs are capable to proliferate, migrate, adopt neural phenotypes, and finally integrate into neural circuits, leading to neural repair.
In fact, the inadequate availability of endogenous NSCs limits CNS from self-repair in response to diseases or injuries. Similarly, difficulties in the application of NSCs transplants reduce their therapeutic efficacy. Besides well-known issues of immunological rejection, reliable sources and ethical pressure, limited proliferation, migration, differentiation, and viability of NSCs following transplantation are more challenging. For instance, literature has shown that transplanted NSCs survive for maximum several weeks Jablonska et al. These limitations have impelled research workers to explore optimized and feasible protocols for NSC-based therapies.
Numerous studies have revealed that the ES plays a potential regenerative role in memory Liu et al. These findings may deepen our understanding of cell replacement therapies following CNS insults and then drive the translation of NSC therapies combined with ES from animal experiments into the clinic settings. Thus, we will primarily focus on the use of endogenous and exogenous electrical currents in the development of NSC-based approaches. Endogenous electrical currents have been discovered in the normal and injured brains. These currents play an important role in biological functions, such as promotion of neural tube formation Hotary and Robinson, , induction of axonal regeneration Borgens et al.
For instance, Cao et al. Then they identified the applied electrical currents of physiological strength as directional signals for neuroblast migration in vitro and in brain slices. Data showed that directedness value of migration in electric field group is 2—2. The directedness value was used to quantify directional migration of neuroblasts toward the cathode.
Endogenous electrical currents also occur in pathological conditions like SCI or epilepsy. Epilepsy is characterized by non-synchronous brain electrical activity. Thus, these authors preclude the possibility of injury-induced neurogenesis. However, it is unclear whether enhanced neurogenesis results in structure changes and recurrent seizures. From a regenerative standpoint, the results indicate that electrical currents could be engineered to provide directional attractive cues for driving NSC migration or regulating other cell behaviors.
Here come two questions. Whether exogenous electrical fields EFs can imitate endogenous signals? Can NSCs exhibit similar response to exogenous electrical cues? It is well established that exogenous EFs have a positive influence on cell migration known as galvanotaxis or electrotaxis since s.
More specifically, the cultured neural crest cells and embryonic cells move toward the cathode under the stimulation of electrical cues Nuccitelli and Erickson, ; Stump and Robinson, The major difference among these publications is the various signaling pathways mediating cell mobilization. This gives hints that chemical means can be applied to NSC mobilization. If possible, results should be confirmed in the further animal experiments and even human trials. Invasive ES always involves the usage of an electrode implantation into the brain or neuromuscle. However, the neurobiological mechanisms remain largely elusive.
Some researchers propose that it potentially increases hippocampal neurogenesis. For example, some authors reported that improvements of cognitive function are facilitated by the stimulation of medial septum Jeong et al. In , Liu et al. At the molecular level, genes NeuN, Dcx, Angpt2, and Sa4 related with neurogenesis, neuronal differentiation, and migration in the neurogenic zones are upregulated.
Introduction
Besides proliferation, Stone et al. Critically, memory improvement is neurogenesis-dependent, for the effects can be blocked by temozolamide, a known inhibitor of neurogenesis Stone et al. However, enhanced anxiety-related mice do not respond sensitively to selective-serotonin reuptake inhibitors, while normal anxiety-related mice do Schmuckermair et al. Thus, the reliability of enhanced anxiety-related animal models needs verification. Since the response to ES is dependent on time, voltage, interspecies, tissue origins, and others, investigators cannot deduce analogous neural plasticity in human from animal experiments.
Short-duration stimulation is involved in the basic experiments, whereas sustained stimulation is applied in clinical settings Stone et al. Whether chronic stimulation strengthens neurogenesis remains explored. In addition, other possible mechanisms, like modulation of network activity and synaptic inhibition, may attribute to the effects of DBS.
Nevertheless, DBS has vital implications for endogenous repair of the impaired brain. Functional Electrical Stimulation FES uses electrical currents to restore the function of the paralyzed muscles caused by SCI, stroke, and other neurological diseases. Xiang and his coworkers observed that FES increases the number of NPCs in the known neurogenic niches in acute stroke rats Xiang et al. Another study also indicated that FES is beneficial for protecting cortical functions partly because it supports the reorganization of neural tissue and compensates for the lost neurons in ischemic conditions Liu et al.
EA is the combination of traditional acupuncture and a small electric current to achieve functional recovery by stimulating certain acupoints. The electric current is generated by a device, which is attached to the needles. And the needles are inserted at acupoints. Studies have revealed that EA can improve neurobehaviors in the models of stroke Yang et al. Neurogenesis is wildly investigated in the cerebral ischemia model. A latest publication unraveled the molecular mechanism underlying neural regeneration elicited by EA Kim et al.
In another study, the effects of EA on attenuating the decrease of proliferating cells and differentiated neuroblasts have also been proved to be correlated with increasing BDNF levels Chung et al. The data indicated that BDNF plays a definitive role in the downstream pathway of neurogenesis. Compared with invasive ES, non-invasive electrical stimulation NIES does not require surgical procedures and has relative fewer side effects.
It utilizes electrical or electromagnetic currents to target the brain through the scalp, leading to the change of cortical excitability, neuronal metabolisms, or neurotransmitter. Despite the fact that TMS has received the approval from Food and Drug Administration FDA for clinical applications since , the underlying mechanism is largely puzzling. It is widely accepted that TMS augments cerebral physiology through balancing excitatory and inhibitory activity in specific brain regions.
While a relevant research has examined that TMS strengthens neurogenesis in healthy rats Ueyama et al.
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That is not in line with the findings of Czeh et al. It is assumed that non-optimal TMS parameters may partly explain the insignificant effects of TMS on hippocampal neurogenesis. The differences between these two studies are frequency 25 vs. In the subsequent studies, TMS can promote neurogenesis under pathological conditions, accompanied by behavior improvements Guo et al. Therefore, we classified deep-brain magnetic stimulation as TMS. Zhang and his colleagues provided evidence that TMS not only boosts the number of NPCs in a rat model of stress disorders but also facilitates the dendritic development of newborn neurons, implying that newborn neurons may probably integrate into existing neural networks Zhang et al.
How does TMS influence neurogenesis? Actually, little work has explored the mechanisms of TMS on neurogenesis. So, TMS can be a potential strategy for neural regeneration. In some animal experiments, TMS could promote neural plasticity whether such effects can also be observed in human trials that remain to be examined. A recent clinical trial has shown that there are also similar therapeutic effects on depressed patients. Different from previous animal investigations, the clinical trial conducted by Furtado et al.
Increased amygdala volumes and unchanged hippocampus volumes are found in TMS responders. There is evidence that volumetric increases are associated with structural plasticity in the CNS Joshi et al. However, it is not clear whether the volumetric changes are induced by TMS or psychotropic medications, in that the study did not have a control group and all the enrolled individuals took the medications. So, the relationship between nerve regeneration and TMS should deserve sustained attention in future.
Transcranial direct current stimulation, another commonly used NIES technique, was introduced by Priori et al. This technique delivers low currents to the brain areas of interest through electrodes over the scalp and then ameliorates negative symptoms of CNS illness by altering cortical excitability. Additionally, it is indicated that the neural regeneration can be promoted by the tDCS, thereby resulting in the improvement of neurological function.
Though anodal tDCS induces an almost double increase in the migratory activity of engrafted NSCs compared with sham and cathodal stimulation group, the migration is undirected. The cell migration distance is about 1. The authors assumed that short-range migrating capability of implanted NSCs is restrained by the surrounding microenvironment. Perhaps, the mobility of endogenous NSCs is more susceptible to galvanotactic clues. It is not consistent with the findings of Keuters and his teammates. These findings need to be replicated, and more research needs to conduct to understand how tDCs affects the migration of NSCs, and unravel their underlying electrophysiological mechanisms.
Preclinical observations suggest that adult brain can compensate for some lost neurons or tissues via enhanced endogenous activated neurogenesis or NSCs grafts. NSCs are through three distinct steps, namely proliferation, migration, and differentiation, to replenish the damaged neurons or tissues.
Can we help the brain to regenerate?
Actually, the greatest challenges concerning application of NSCs are not only long-term cell survival, but also low proliferation, differentiation, and migration rates. There is ample evidence illustrating these hurdles. Given the complexity of CNS microenvironment, though NSCs are transplanted into an ischemic rat model, they just survive robustly about Compared with medial coordinates, lateral coordinates are closer to lesion core.
Even though NSCs survive, they have to differentiate to functional neurons to take effect. So, it is necessary to improve the poor-survival rate of newborn cells before NSC-based strategy can be applied in the clinical settings. Finally, although Kelly et al. However, other data presented that only As outlined above, researchers should introduce efficient methods to increase viability, differentiation, and migration properties of NSCs, overcoming the above mentioned obstacles.
How stem cells can help to repair the damaged brain.
With the prevalence of ES application in experimental studies and clinical cases, research teams raise that it can act as an alternative modulator of NSC biology. Ongoing work has shown that ES can influence cytobiology parameters, such as growth, migration, differentiation, proliferation, and even morphology of NSCs invasively or non-invasively. Apparently, non-invasive ES has superiority over invasive ones. Most invasive ES but EA always requires implantation of a medical device with the operation of a neurosurgeon, which is time-and technology-depending.
It is worthwhile to note that DBS has diminished response over time to brain stimulation. Conversely, non-invasive ES is convenient for repeated operations. Moreover, tDCS, a portable device with simplicity of its mode of action, offers the possibility of use as a home-based treatment Page et al. Similar to ES, biomaterial engineering in enhancing regenerative potential of CNS has also been documented. Biomaterials, such as electrically conductive substrates polymers and nanomaterials , have gradually earned attention.
NSCs cultured on nanomaterials, namely carbon nanotubes, sprout more neuritis, and have a higher percentage of neuronal differentiation than those on conventional tissue culture plates Huang et al. No multipotent factors directing differentiation toward neuron lineage are added to culture medium. Summing up, these biomaterials exert an impact on cultivated NSC differentiation, which is innovative while is still in its infancy.
More work is needed to elucidate how biomaterials drive cellular changes in the following years. Since physical stimuli do play an instructive role in neurogenesis, do chemical stimuli facilitate regenerative capacity of CNS?
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Growing evidences reveal that drug-like molecules regulate NSC-related processes. The pharmacological manipulation aims at epigenetic modifications or signaling pathways, both of which determine NSC development by influencing the property of protein Lairson et al. Different from gene-based therapy, epigenetics regulate gene expression but cause no changes in the DNA sequence, minimizing the risk of gene mutation.
Molecules targeting at epigenetic modifications include histone methylation, DNA methylation Swaminathan et al.
The Ramous lab recently reported a new-discovered long non-coding RNA. Whether these molecules act on epigenetics or signaling pathways provide insights into complex regenerative processes. Challenges must be overcome to achieve successful cell replacement in the brain. Fortunately, exogenous ES, biomaterials, chemical stimuli as well as other cues can control NSC behaviors migration, viability, differentiation, and proliferation. Due to their electrically conductive nature, nanomaterials and polymers can respond to ES. So, we presume that electricity combined with biomaterials may improve its electrophysiological features, which is beneficial for electricity to reach functional areas of deep brain even when the electrodes are placed on the scalp.
Moreover, biomaterials can change a hostile microenvironment to a friendly microenvironment as they are able to deliver trophic factors for NSCs or endogenous tissues Mahoney and Anseth, Or are there other Mesenchymal SC-lines of interest? Noting the subjective nature of most brain-related assessment rating scales, I reckon that one of the biggest challenges to the acceptance of any SC use is to find objective methods that prove any improvements noted in cognition or behavior following therapy are not simply those of a placebo effect.
Would value your comments. Hi Roger, Thank you for your questions. Diseases affecting the brain are typically a mix of genetic, environmental and lifestyle factors. Another promising approach is to actually correct a faulty gene. Techniques like next generation sequencing could see, in the future an evaluation of the risk of a patients stem cells becoming diseased or not.
The positive side of your own stem cells is no rejection by the immune system. Using a donor stem cell does involve a long period of immune suppressants, as the immune system will see the new stem cells as foreign and potentially attack them. Screening the stem cells might also be useful here, as the genetic make-up of the donated cells could also include disease related mutations. Mesenchymal cells such as bone marrow derived stem cells have been used. Interesting work is being done with inducing fibroblasts to become neural stem cells.
Cell Therapy Stem Cells And Brain Repair Contemporary Neuroscience
I am sure further advances are not far off. Very recent news tells of a reversal to paralysis. Standard clinical assessments apply. Extensive testing in models before patient trials gives details of how the stem cells behave in situ. These studies need to be done before clinical trial and the subjective assessments they typically use.
In some cases, such as strokes, MRI imaging does give an assessment of damage to the brain. The first UK clinical trial, using stem cells for acute stroke patients did show a response using clinical assessments. This is very promising. It would be great to have a blog article written on neuro-diagnostics.
Hi just wondering if this could potentially cure scarred tissue e. Hi Dave This is an excellent resource for patients looking for info on stem cell therapies: