Implications of regional identity for neural stem and progenitor cell transplantation in the injured or diseased nervous system

Neural stem and progenitor cell(NSPC)transpla ntation has emerged as a promising therapeutic strategy for replacing lost neuronal populations and repairing damaged neural circuits following nervous system injury and disease.A great deal of experimental work has investigated the biology of NSPC grafting in preclinical animal models;more recently.

Nucleoside modified mRNA-lipid nanoparticles as a new delivery platform for the repair of the injured spinal cord

Spinal cord injury and treatment opportunities:The adult mammalian spinal cord has a very limited capacity for spontaneous regeneration due to various intrinsic molecular and cellular factors.Although the spinal cord neurons have the capacity to regenerate their axons,the expression of growth inhibitory factors,lack or suppression of proper guidance cues,and profound inflammatory responses do not permit successful regeneration(Khyeam et al.,2021).

Low-frequency pulsed electromagnetic field pretreated bone marrow-derived mesenchymal stem cells promote the regeneration of crush-injured rat mental nerve

Bone marrow-derived mesenchymal stem cells （BMSCs） have been shown to promote the regeneration of injured peripheral nerves. Pulsed electromagnetic field （PEMF） reportedly promotes the proliferation and neuronal differentiation of BMSCs. Low-frequency PEMF can induce the neuronal differentiation of BMSCs in the absence of nerve growth factors. This study was designed to investigate the effects of low-frequency PEMF pretreatment on the proliferation and function of BMSCs and the effects of low-frequency PEMF pre-treated BMSCs on the regeneration of injured peripheral nerve using in vitro and in vivo experiments.In in vitro experiments, quantitative DNA analysis was performed to determine the proliferation of BMSCs, and reverse transcription-polymerase chain reaction was performed to detect S100 （Schwann cell marker）, glial fibrillary acidic protein （astrocyte marker）, and brain-derived neurotrophic factor and nerve growth factor （neurotrophic factors） mRNA expression. In the in vivo experiments, rat models of crush-injured mental nerve established using clamp method were randomly injected with low-frequency PEMF pretreated BMSCs, unpretreated BMSCs or PBS at the injury site （1 × 106 cells）. DiI-labeled BMSCs injected at the injury site were counted under the fluorescence microscope to determine cell survival. One or two weeks after cell injection, functional recovery of the injured nerve was assessed using the sensory test with von Frey filaments. Two weeks after cell injection, axonal regeneration was evaluated using histomorphometric analysis and retrograde labeling of trigeminal ganglion neurons. In vitro experiment results revealed that low-frequency PEMF pretreated BMSCs proliferated faster and had greater mRNA expression of growth factors than unpretreated BMSCs. In vivo experiment results revealed that compared with injection of unpretreated BMSCs, injection of low-frequency PEMF pretreated BMSCs led to higher myelinated axon count and axon density and more DiI-labeled neurons in the trigeminal ganglia, contributing to rapider functional recovery of injured mental nerve. These findings suggest that low-frequency PEMF pretreatment is a promising approach to enhance the efficacy of cell therapy for peripheral nerve injury repair.

A Two-Parameter Description for the Injury Risk of Flash Bangs with Uncertainty

We study the random injury outcome caused by multiple flash bang submunitions on a crowd. We are particularly interested in the fluctuations in injury outcome among individual realizations. Previously, to simulate the distribution of the actual number of injured, we developed a comprehensive Monte Carlo model. While the full computational model is important for thorough theoretical investigations, in practical operations, it is desirable to characterize the phenomenological behavior of injury outcome using a concise model with only one or two parameters. Conventionally, the injury outcome is indicated by the average fraction of injured, which is called the risk of significant injury (RSI). The single metric RSI description fails to capture fluctuations in the injury outcome. The number of injured in the crowd is influenced by many random factors: the aiming error of flash bang mortar, the dispersion of submunitions after mortar burst, the amount of acoustic dose reaching individual subjects, and the biovariability of individual subjects’ reactions to a given acoustic dose. We aim to include these random factors properly and concisely. In this study, we represent the random injury outcome as a compound binomial model, in which the hidden injury probability is drawn from a two-parameter model distribution. We formulate and examine six model distributions for the injury probability. The best performer is a mixture of uniform and triangle distributions, parameterized by (RSI, dp) where dp is the standard deviation of the hidden injury probability. This mixture model predicts the behavior of injury outcome with uncertainty, based solely on the two parameters (RSI, dp) in the flash bang description. For example, we can predict the probability of the injury outcome not exceeding a prescribed tolerance. We advocate the adoption of this two-parameter characterization for flash bangs to replace the single-parameter RSI description. Whenever we need to give a high level coarse description of a flash bang situation, we state that the injury risk is represented by (RSI, dp).

MRS and diffusion tensor image in mild traumatic brain injuries

Objective:To analyze characters of magnetic resonance spectroscopy(MRS) and diffusion tensor imaging(DTI) in the diagnosis of mild trauma brain injuries(MTBI) in frontal lobe and to compare with conventional magnetic resonance imaging(MRI).Methods:A total of 21 patients were selected,who all aged 12-51 years old and had injury within 24 hours.Computer tomography (CT) and the Glasgow Coma Scale were used to evaluate the degree of injury.All patients were diagnosed as MTBI,and 19 had conventional MRI,MRS and DTI.The major parameters of MRS were Probe-P sequence,TE= 144 or 35 ms,and both single voxel spectrum and chemical shift imging were included.The major parameters of DTI were diffusion directions =15,b value = 1000 s/mm^2. Frational anisotropic(FA) map and average ADC map were obtained to evaluate DTI result. Positive deletion ratio was observed and the imaging changes were compared between injured side and normal side.Results:All 21 patients had CT scan and Glasgow scale.A total of 19 patients had conventional MRI.DTI and MRS.Results of CT and conventional MRI showed no significant abnormality in lobe,and Glasgow scale showed mild type.MRS result showed significant decrease in N-acetyl aspartate(NAA) and NAA/creatine(Cr) in 13 cases(68.4%) (P【0.001),and increase in lactic acid(Lac) in 7 cases(36.8%).FA mapping of the frontal lobe displayed significant changes in 7 cases(36.8%),with 5 out of the 7 cases having increase in FA value.And there was no significant difference in average ADC.Conclusions:MRS and DTI might be more sensible than other methods,such as CT and conventional MRI in diagnosis of MTBI.The particular changes were reduced NAA and increased Lac for MRS.and increased FA values for DTI.

Beneficial effects of BV2 cell on proliferation and neuron-differentiating of mesenchymal stem cells in the circumstance of injured PC12 cell supernatant

Objective The microglias is the representative of immune cells in the brain. It plays dual roles of both repairing and damaging in injured nervous system, and works as an inevitable component of the circumstance of injured neurons. This study was aiming at the effects of the microglias on the biological activities of mesenchymal stem cells （MSCs） in the circumstance of injured neurons. Methods MSCs were obtained by primary culture. We adopted PC12 cells （PC12） and BV2 cells （BV2） to substitute for neurons and microglias, respectively. PC12 were injured by aged Aβ1-40 and the supernatant of the injured PC12 was used to set up the circumstance of injured neurons. Transwells were used for co-culture of BV2 and MSCs, which allowed the independent detection of cells after co-culture. Immunofluorescence was used to identify MSCs and neuron-differentiating cells with CD44 and neuron specific enolase （NSE） staining, respectively. MTT assay was adopted to measure the proliferation. Results In the circumstance of both BV2 presence and injured PC 12 supernatant incubation, either the proliferation or the differentiation of MSCs reached the highest, which seemed to be contradictory, but we gave our explanations. With the BV2 co-culture, the proliferation of MSCs tend to be higher, but the neuron-differentiating MSCs were similar to those incubated without BV2 co-culture either in normal or injured in PC12 supernatant. With the incubation of injured PC12 supernatant, the neuron-differentiating cells were significantly higher than that of control （P 〈 0.05）. Conclusion In the circumstance of injured neurons, microlgias tend to promote the MSCs proliferation. Although not helpful in neuron-differentiating, microglias did not exert any negative effect either.

Neural cell injury microenvironment induces neural differentiation of human umbilical cord mesenchymal stem cells

This study aimed to investigate the neural differentiation of human umbilical cord mesenchymal stem cells （hUCMSCs） under the induction of injured neural cells. After in vitro isolation and culture, passage 5 hUCMSCs were used for experimentation, hUCMSCs were co-cultured with normal or AI31.4o-injured PC12 cells, PC12 cell supernatant or PC12 cell lysate in a Transwell co-culture system. Western blot analysis and flow cytometry results showed that choline acetyltransferase and microtubule-associated protein 2, a specific marker for neural cells, were expressed in hUCMSCs under various culture conditions, and highest expression was observed in the hUCMSCs co-cultured with injured PC12 cells. Choline acetyltransferase and microtubule-associated protein 2 were not expressed in hUCMSCs cultured alone （no treatment）. Cell Counting Kit-8 assay results showed that hUCMSCs under co-culture conditions promoted the proliferation of injured PC12 cells. These findings suggest that the microenvironment during neural tissue injury can effectively induce neural cell differentiation of hUCMSCs. These differentiated hUCMSCs likely accelerate the repair of injured neural ceils.

Bridging the injured spinal cord with neural stem cells

Spinal cord injury （SCI） damages not only the gray matter neurons, but also the white matter axonal tracts that carry signals to and from the brain, re- suiting in permanent loss of function below injury. Neural stem cells （NSCs） have high therapeutic potential for reconstruction of the injured spinal cord since they can potentially fnrm neuronal relays to bridge functional con-nectivity between separated spinal cord segments. This requires host axonal regeneration into and connectivity with donor neurons, and axonal growth and connectivity of donor neurons to host central nervous system （CNS） circuitry. In this mini-review, we will discuss key studies that explore novel neuronal relay formation by grafting NSCs in models of SCI, with emphasis on long-distance axonal growth and connectivity of NSCs grafted into in-jured spinal cord.

Mechanisms of electroacupuncture effects on acute cerebral ischemia/reperfusion injury:possible association with upregulation of transforming growth factor beta 1

Electroacupuncture at the head acupoints Baihui（GV20） and Shuigou（GV26） improves recovery of neurological function following ischemic cerebrovascular events,but its mechanism remains incompletely understood.We hypothesized that the action of electroacupuncture at these acupoints is associated with elevated serum levels of transforming growth factor beta 1（TGF-β1）.To test this,we established a rat model of cerebral ischemia by middle cerebral artery occlusion.Electroacupuncture was performed at Baihui and Shuigou with a “dispersedense” wave at an alternating frequency of 2 and 150 Hz,and at a constant intensity of 3 m A.Each electroacupuncture session lasted 30 minutes and was performed every 12 hours for 3 days.Neurological severity scores were lower in injured rats after acupuncture than in those not subjected to treatment.Furthermore,serum level of TGF-β1 was greater after electroacupuncture than after no treatment.Our results indicate that electroacupuncture at Baihui and Shuigou increases the serum level of TGF-β1 in rats with acute cerebral ischemia/reperfusion injury,and exerts neuroprotective effects.

Protective effects of ginsenoside Rg1 against hydrogen peroxide-induced injury in human neuroblastoma cells

The active ingredient of ginseng,ginsenosides Rg1,has been shown to scavenge free radicals and improve antioxidant capacity.This study hypothesized that ginsenosides Rg1 has a protective role in human neuroblastoma cells injured by H2O2.Ginsenosides Rg1 at different concentrations（50 and 100 μM） was used to treat H2O2（150 μM）-injured SH-SY5 Y cells.Results demonstrated that ginsenoside Rg1 elevated the survival rate of SH-SY5 Y cells injured by H2O2,diminished the amount of leaked lactate dehydrogenase,and increased superoxide dismutase activity.Ginsenoside Rg1 effectively suppressed caspase-3 immunoreactivity,and contributed to heat shock protein 70 gene expression,in a dose-dependent manner.These results indicate that ginsenoside Rg1 has protective effects on SH-SY5 Y cells injured by H2O2 and that its mechanism of action is associated with anti-oxidation and the inhibition of apoptosis.

Mechanisms underlying the promotion of functional recovery by deferoxamine after spinal cord injury in rats

Deferoxamine, a clinically safe drug used for treating iron overload, also repairs spinal cord injury although the mechanism for this action remains unknown. Here, we determined whether deferoxamine was therapeutic in a rat model of spinal cord injury and explored potential mechanisms for this effect. Spinal cord injury was induced by impacting the spinal cord at the thoracic T10 vertebra level. One group of injured rats received deferoxamine, a second injured group received saline, and a third group was sham operated. Both 2 days and 2 weeks after spinal cord injury, total iron ion levels and protein expression levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β and the pro-apoptotic protein caspase-3 in the spinal cords of the injured deferoxamine-treated rats were significantly lower than those in the injured saline-treated group. The percentage of the area positive for glial fibrillary acidic protein immunoreactivity and the number of terminal deoxynucleotidyl transferase d UTP nick end labeling-positive cells were also significantly decreased both 2 days and 2 weeks post injury, while the number of Neu N-positive cells and the percentage of the area positive for the oligodendrocyte marker CNPase were increased in the injured deferoxamine-treated rats. At 14–56 days post injury, hind limb motor function in the deferoxamine-treated rats was superior to that in the saline-treated rats. These results suggest that deferoxamine decreases total iron ion, tumor necrosis factor-α, interleukin-1β, and caspase-3 expression levels after spinal cord injury and inhibits apoptosis and glial scar formation to promote motor function recovery.

Transplanting neural progenitors to build a neuronal relay across the injured spinal cord

Cellular transplantation for repair of spinal cord injury is a prom- ising therapeutic strategy that includes the use of a variety of neural and non-neural cells isolated or derived from embryonic and adult tissue as well as embryonic stem cells and induced plu- ripotent stem cells. In particular, transplants of neural progenitor cells （NPCs） have been shown to limit secondary injury and scar formation and create a permissive environment in the injured spinal cord through the provision of neurotrophic molecules and growth supporting matrices that promote growth of injured host axons. Importantly, transplants of NPC are unique in their poten- tial to replace lost neural cells - including neurons, astrocytes,

Brain injury in combination with tacrolimus promotes the regeneration of injured peripheral nerves

Both brain injury and tacrolimus have been reported to promote the regeneration of injured peripheral nerves. In this study, before transection of rat sciatic nerve, moderate brain contusion was（or was not） induced. After sciatic nerve injury, tacrolimus, an immunosuppressant, was（or was not） intraperitoneally administered. At 4, 8 and 12 weeks after surgery, Masson＇s trichrome, hematoxylin-eosin, and toluidine blue staining results revealed that brain injury or tacrolimus alone or their combination alleviated gastrocnemius muscle atrophy and sciatic nerve fiber impairment on the experimental side, simultaneously improved sciatic nerve function, and increased gastrocnemius muscle wet weight on the experimental side. At 8 and 12 weeks after surgery, brain injury induction and/or tacrolimus treatment increased action potential amplitude in the sciatic nerve trunk. Horseradish peroxidase retrograde tracing revealed that the number of horseradish peroxidase-positive neurons in the anterior horn of the spinal cord was greatly increased. Brain injury in combination with tacrolimus exhibited better effects on repair of injured peripheral nerves than brain injury or tacrolimus alone. This result suggests that brain injury in combination with tacrolimus promotes repair of peripheral nerve injury.

Transplantation of human adipose tissue-derived stem cells for repair of injured spiral ganglion neurons in deaf guinea pigs

Excessive noise, ototoxic drugs, infections, autoimmune diseases, and aging can cause loss of spiral ganglion neurons, leading to permanent sensorineural hearing loss in mammals. Stem cells have been confirmed to be able to differentiate into spiral ganglion neurons. Little has been reported on adipose tissue-derived stem cells（ADSCs） for repair of injured spiral ganglion neurons. In this study, we hypothesized that transplantation of neural induced-human ADSCs（NI-h ADSCs） can repair the injured spiral ganglion neurons in guinea pigs with neomycin-induced sensorineural hearing loss. NI-h ADSCs were induced with culture medium containing basic fibroblast growth factor and forskolin and then injected to the injured cochleae. Guinea pigs that received injection of Hanks＇ balanced salt solution into the cochleae were used as controls. Hematoxylin-eosin staining showed that at 8 weeks after cell transplantation, the number of surviving spiral ganglion neurons in the cell transplantation group was significantly increased than that in the control group. Also at 8 weeks after cell transplantation, immunohistochemical staining showed that a greater number of NI-h ADSCs in the spiral ganglions were detected in the cell transplantation group than in the control group, and these NI-h ADSCs expressed neuronal markers neurofilament protein and microtubule-associated protein 2. Within 8 weeks after cell transplantation, the guinea pigs in the cell transplantation group had a gradually decreased auditory brainstem response threshold, while those in the control group had almost no response to 80 d B of clicks or pure tone burst. These findings suggest that a large amount of NI-h ADSCs migrated to the spiral ganglions, survived for a period of time, repaired the injured spiral ganglion cells, and thereby contributed to the recovery of sensorineural hearing loss in guinea pigs.

Neural regeneration after spinal cord injury treatment by lavandula angustifolia and human umbilical mesanchymal stem cell transplantation

Spinal cord injury（SCI）is one of the most common causes of paralysis worldwide because the loss of neurons and axons causes permanent neurological deficits which could have influences on quality of life of patients,their family,and society.The complex pathophysiology of SCI,especially the secondary injury cascade,blocks complete recovery after SCI（Dumont et al.,2001）.

Application and implications of polyethylene glycol-fusion as a novel technology to repair injured spinal cords

Conventional vs. polyethylene glycol （PEG）-fusion tech- nologies to repair severed spinal axons： Most spinal cord injuries （SCIs） involve cutor crush-severance of spinal tract axons in the central nervous system （CNS）. Clinical out- comes after CNS axonal severance is very poor because proximal segments of CNS axons lack a suitable environment for outgrowth （Kakulas, 1999; Fitch and Silver, 2008; Rowland et al., 2008; Kwon et al., 2010） and therefore do not naturally regenerate （Ramon y Caial, 1928）. Current strategies to try to increase behavioral recovery after SCI are focused on en- hancing the environment for axonal outgrowth.

Small Interfering RNA Targeting TNF-α Gene Significantly Attenuates Renal Ischemia-Reperfusion Injury in Mice

Tumor necrosis factor-alpha（TNF-α） has been found to be centrally involved in the development of ischemia-reperfusion injury（IRI）-induced inflammation and apoptosis. Knockdown of TNF-α gene using small interfering RNA（si RNA） may protect renal IRI. Renal IRI was induced in mice by clamping the left renal pedicle for 25 or 35 min. TNF-α si RNA was administered intravenously to silence the expression of TNF-α. The therapeutic effects of si RNA were evaluated in terms of renal function, histological examination, and overall survival following lethal IRI. A single systemic injection of TNF-α si RNA resulted in significant knockdown of TNF-α expression in ischemia-reperfusion injured kidney. In comparison with control mice, levels of BUN and serum creatinine were significantly reduced in mice treated with si RNA. Pathological examination demonstrated that tissue damage caused by IRI was markedly reduced as a result of TNF-α si RNA treatment. Furthermore, survival experiments showed that nearly 90% of control mice died from lethal IRI, whereas more than 50% of si RNApretreated mice survived until the end of the eight-day observation period. We have demonstrated for the first time that silencing TNF-α by specific si RNA can significantly reduce renal IRI and protect mice against lethal kidney ischemia, highlighting the potential for si RNA-based clinical therapy.

Physical interactions between activated microglia and injured axons:do all contacts lead to phagocytosis?

Axonal injury is a pathological hallmark of both head injury and inflammatory-mediated neurological disorders,including multiple sclerosis（Schirmer et al.,2013）.Such axonal disruptions and/or disconnections typically result in proximal axonal segments that remain in continuity with the neuronal somawhile losing contact with their distal targets.

Recovery of multiply injured ascending reticular activating systems in a stroke patient

Consciousness is controlled by ular activating system （ARAS）. lower and upper parts between activation of the ascending retic- The ARAS consists mainly of the the thalamus and cerebral cortex （Edlow et al., 2012; Yeo et al., 2013; Jang et al., 2014）. Because the ARAS is composed of several neuronal circuits connecting the brainstem to the cortex. These neuronal connections begin from the reticular formation （RF） of the brainstem and the intralaminar nucleus of thalamus to the cerebral cortex （Gosseroes et al., 2011）. In addition, the ARAS system also includes several brainstem nuclei （such as dorsal raphe, locus coeruleus, pedun-culopontine nucleus, median raphe and parabrachial nucleus）, non-specific thalamic nuclei, hypothalamus, and basal forebrain （Fuller et al., 2011）.

Recovery of an injured corticospinal tract by subcortical peri-lesional reorganization in a patient with intracerebral hemorrhage

The corticospinal tract （CST） is a neural tract responsible for motor function in the human brain. It is mainly related to hand movements （Iang, 2014）. Therefore, recovery of an injured CST contributes to good recovery in stroke patients and a thorough knowledge of the recovery mechanism regarding an injured CST is required for successful brain rehabilitation.