Neural Stem Cells For Treatment Research Articles

The bibliometric analysis on neural stem cells in the treatment of traumatic brain injury

Background: Traumatic brain injury (TBI) is caused by a blow or a penetrating injury to the head, which can disrupt normal brain function and is life-threatening to the patient. Neural stem cells can play a certain neuroprotective role in TBI with its enormous self-renewal and differentiation capacity. Therefore, this paper reviews the research progress of neural stem cells in the treatment of TBI based on bibliometric analysis. Methods: Web of Science Core Collection database was used according to the search formula TS = ("Neural stem cell") AND TS = ("Traumatic Brain Injury") AND Publication Date = (January 1, 2001 to December 31, 2023) to find 174 relevant articles. Subsequently, bibliometrics analysis was performed to know the contributions of countries, institutions, journals, and current trends and research hotspots by using Vosviewer and Citespace software. Results: The results suggest that the current research trend in neural stem cell treatment of TBI is focusing on neurogenesis. The most influential countries are the United States, China, and Japan with the highest publications. The impactful institutions and authors are also distributed among these countries. Conclusions: This review summarizes the current advances in neural stem cell treatment of TBI, which is helpful for future research guidance.

Routes and methods of neural stem cells injection in cerebral ischemia.

Cerebral ischemia is a serious cerebrovascular disease with the characteristics of high morbidity, disability, and mortality. Currently, stem cell therapy has been extensively applied to a wide range of diseases, including neurological disorders, autoimmune deficits, and other diseases. Transplantation therapy with neural stem cells (NSCs) is a very promising treatment method, which not only has anti-inflammatory, antiapoptotic, promoting angiogenesis, and neurogenesis effects, but also can improve some side effects related to thrombolytic therapy. NSCs treatment could exert protective effects in alleviating cerebral ischemia-induced brain damage and neurological dysfunctions. However, the different injection routes and doses of NSCs determine diverse therapeutic efficacy. This review mainly summarizes the various injection methods and injection effects of NSCs in cerebral ischemia, as well as proposes the existing problems and prospects of NSCs transplantation.

Spinal Cord Injury: Pathophysiology, Neural Stem Cell Treatment and Its Combination with Other Strategies

Spinal Cord Injury: Pathophysiology, Neural Stem Cell Treatment and Its Combination with Other Strategies

Induced neural stem cells suppressed neuroinflammation by inhibiting the microglial pyroptotic pathway in intracerebral hemorrhage rats

Intracerebral hemorrhage usually manifests as strong neuroinflammation and neurological deficits. There is an urgent need to explore effective methods for the treatment of intracerebral hemorrhage. The therapeutic effect and the possible mechanism of induced neural stem cell transplantation in an intracerebral hemorrhage rat model are still unclear. Our results showed that transplantation of induced neural stem cells could improve neurological deficits by inhibiting inflammation in an intracerebral hemorrhage rat model. Additionally, induced neural stem cell treatment could effectively suppress microglial pyroptosis, which might occur through inhibiting the NF-κB signaling pathway. Induced neural stem cells could also regulate the polarization of microglia and promote the transition of microglia from pro-inflammatory phenotypes to anti-inflammatory phenotypes to exert their anti-inflammatory effects. Overall, induced neural stem cells may be a promising tool for the treatment of intracerebral hemorrhage and other neuroinflammatory diseases.

Mathematical modeling of therapeutic neural stem cell migration in mouse brain with and without brain tumors.

Neural stem cells (NSCs) offer a potential solution to treating brain tumors. This is because NSCs can circumvent the blood-brain barrier and migrate to areas of damage in the central nervous system, including tumors, stroke, and wound injuries. However, for successful clinical application of NSC treatment, a sufficient number of viable cells must reach the diseased or damaged area(s) in the brain, and evidence suggests that it may be affected by the paths the NSCs take through the brain, as well as the locations of tumors. To study the NSC migration in brain, we develop a mathematical model of therapeutic NSC migration towards brain tumor, that provides a low cost platform to investigate NSC treatment efficacy. Our model is an extension of the model developed in Rockne et al. (PLoS ONE 13, e0199967, 2018) that considers NSC migration in non-tumor bearing naive mouse brain. Here we modify the model in Rockne et al. in three ways: (i) we consider three-dimensional mouse brain geometry, (ii) we add chemotaxis to model the tumor-tropic nature of NSCs into tumor sites, and (iii) we model stochasticity of migration speed and chemosensitivity. The proposed model is used to study migration patterns of NSCs to sites of tumors for different injection strategies, in particular, intranasal and intracerebral delivery. We observe that intracerebral injection results in more NSCs arriving at the tumor site(s), but the relative fraction of NSCs depends on the location of injection relative to the target site(s). On the other hand, intranasal injection results in fewer NSCs at the tumor site, but yields a more even distribution of NSCs within and around the target tumor site(s).

Neural stem cell treatment for perinatal brain injury: A systematic review and meta-analysis of preclinical studies.

Perinatal brain injury can lead to significant neurological and cognitive deficits and currently no therapies can regenerate the damaged brain. Neural stem cells (NSCs) have the potential to engraft and regenerate damaged brain tissue. The aim of this systematic review was to evaluate the preclinical literature to determine whether NSC administration is more effective than controls in decreasing perinatal brain injury. Controlled interventional studies of NSC therapy using animal models of perinatal brain injury were identified using MEDLINE and Embase. Primary outcomes were brain infarct size, motor, and cognitive function. Data for meta‐analysis were synthesized and expressed as standardized mean difference (SMD) with 95% confidence intervals (CI), using a random effects model. We also reported secondary outcomes including NSC survival, migration, differentiation, and effect on neuroinflammation. Eighteen studies met inclusion criteria. NSC administration decreased infarct size (SMD 1.09; CI: 0.44, 1.74, P = .001; I 2 = 74%) improved motor function measured via the impaired forelimb preference test (SMD 2.27; CI: 0.85, 3.69, P = .002; I 2 = 86%) and the rotarod test (SMD 1.88; CI: 0.09, 3.67, P = .04; I 2 = 95%). Additionally, NSCs improved cognitive function measured via the Morris water maze test (SMD of 2.41; CI: 1.16, 3.66, P = .0002; I 2 = 81%). Preclinical evidence suggests that NSC therapy is promising for the treatment of perinatal brain injury. We have identified key knowledge gaps, including the lack of large animal studies and uncertainty regarding the necessity of immunosuppression for NSC transplantation in neonates. These knowledge gaps should be addressed before NSC treatment can effectively progress to clinical trial.

SCIDOT-20. ADAPTING ENGINEERED CELL THERAPIES TO UNDERSTAND AND OVERCOME GLIOBLASTOMA RESISTANCE USING INTEGRATED IN VIVO AND EX VIVO MODELS

Abstract Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM), yet treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaption of GBM during NSC treatment and develop strategies to convert initial tumor kill into sustained GBM suppression. Using a unique hybrid tumor model treated with human skin-derived induced NSCs (iNSCs) releasing the pro-apoptotic agent TRAIL, we investigated how spatial distribution of tumor and iNSCs affects GBM adaption throughout recurrence. Serial bioluminescent imaging (BLI) was used to track tumor volumes in vivo, while a subset of mice were sacrificed 6, 13, and 20 days post-treatment to harvest brains and generate living ex vivo tissue slices. Live animal imaging showed iNSC-TRAIL treatment rapidly decreased tumor volumes when delivered into the primary tumor mass; however, minimal impact on tumor growth was observed when cells were delivered into distal regions of the brain. In contrast, high-resolution imaging of living brain sections showed extensive impacts of iNSC-TRAIL therapy that could not be visualized with BLI. The living slices showed iNSC-TRAIL treatment into the primary tumor decreased the solid, but not the invasive, tumor burden. Treatment into the lateral ventricles did impact tumor kill and was more effective at treating the invasive tumor burden and maintaining inhibition than treatment into the contralateral parenchyma. We next utilized the living tissue slices to explore the sensitivity of the recurrent tumors to TRAIL. When therapy was applied to slices harboring recurrent tumor, treatment again significantly reduced tumor volumes, suggesting tumors had not acquired TRAIL resistance. These results informed an additional in vivo survival study and subsequent PCR analysis of untreated and recurrent tumors, and combine the fidelity of in vivo studies with the speed and spatial resolution of living brain slice technology.

TMOD-31. ADAPTING ENGINEERED CELL THERAPIES TO UNDERSTAND AND OVERCOME GLIOBLASTOMA RESISTANCE USING INTEGRATED IN VIVO AND EX VIVO MODELS

Abstract Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM), yet treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaption of GBM during NSC treatment and develop strategies to convert initial tumor kill into sustained GBM suppression. Using a unique hybrid tumor model treated with human skin-derived induced NSCs (iNSCs) releasing the pro-apoptotic agent TRAIL, we investigated how spatial distribution of tumor and iNSCs affects GBM adaption throughout recurrence. Serial bioluminescent imaging (BLI) was used to track tumor volumes in vivo, while a subset of mice were sacrificed 6, 13, and 20 days post-treatment to harvest brains and generate living ex vivo tissue slices. Live animal imaging showed iNSC-TRAIL treatment rapidly decreased tumor volumes when delivered into the primary tumor mass; however, minimal impact on tumor growth was observed when cells were delivered into distal regions of the brain. In contrast, high-resolution imaging of living brain sections showed extensive impacts of iNSC-TRAIL therapy that could not be visualized with BLI. The living slices showed iNSC-TRAIL treatment into the primary tumor decreased the solid, but not the invasive, tumor burden. Treatment into the lateral ventricles did impact tumor kill and was more effective at treating the invasive tumor burden and maintaining inhibition than treatment into the contralateral parenchyma. We next utilized the living tissue slices to explore the sensitivity of the recurrent tumors to TRAIL. When therapy was applied to slices harboring recurrent tumor, treatment again significantly reduced tumor volumes, suggesting that tumors had not acquired TRAIL resistance. These results informed an additional in vivo survival study and subsequent PCR analysis of untreated and recurrent tumors, and combine the fidelity of in vivo studies with the speed and spatial resolution of living brain slice technology.

Inhibition of astrocytic differentiation of transplanted neural stem cells by chondroitin sulfate methacrylate hydrogels for the repair of injured spinal cord.

Neural stem cell (NSC) transplantation exerts a therapeutic effect on spinal cord injury (SCI) but is limited to an unregulated differentiation pattern by which NSCs preferentially differentiate into astrocytes, with relatively few neurons. It is well established that the increased NSC-derived astrocytes exhibit aberrant axonal sprouting associated with allodynia-like symptoms of the forepaws. Some strategies have been used to overcome this issue, such as regulation of major pathways, ex vivo gene transfer, and genetic overexpression. However, lack of efficiency, viral vector safety issues and the risk of tumorigenesis have hindered the clinical application of these treatments. Here, we show that astrocytic differentiation of NSCs in vitro and in vivo can be inhibited by encapsulation of cells in a three-dimensional chondroitin sulfate methacrylate (CSMA) hydrogel. When CSMA hydrogels were used to transplant NSCs, the combinatory implant promoted functional recovery and attenuated the hypersensitivity responses of the forepaws. Further analysis showed that transplantation of NSCs within CSMA hydrogels reduced injured cavity areas and promoted neurogenesis rather than fibroglial formation after graft implantation. Furthermore, the treatment prevented allodynia-related CGRP/GAP43-positive nociception due to fibers sprouting into inappropriate lamina regions. Taken together, these findings show that CSMA/NSCs combined transplantation helps prevent adverse side effects of NSCs treatment and promotes recovery of SCI.

Enhanced Delivery of Oncolytic Adenovirus by Neural Stem Cells for Treatment of Metastatic Ovarian Cancer

Oncolytic virotherapy is a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance or neutralization of the virus, which reduces viral access to tumor foci. To overcome this barrier, patient-derived mesenchymal stem cells have been used to deliver virus to tumors, but variability associated with autologous cell isolations prevents this approach from being broadly clinically applicable. Here, we demonstrate the ability of an allogeneic, clonal neural stem cell (NSC) line (HB1.F3.CD21) to protect oncolytic viral cargo from neutralizing antibodies within patient ascites fluid and to deliver it to tumors within preclinical peritoneal ovarian metastases models. The viral payload used is a conditionally replication-competent adenovirus driven by the survivin promoter (CRAd-S-pk7). Because the protein survivin is highly expressed in ovarian cancer, but not in normal differentiated cells, viral replication should occur selectively in ovarian tumor cells. We found this viral agent was effective against cisplatin-resistant ovarian tumors and could be used as an adjunct treatment with cisplatin to decrease tumor burden without increasing toxicity. Collectively, our data suggest NSC-delivered CRAd-S-pk7 virotherapy holds promise for improving clinical outcome, reducing toxicities, and improving quality of life for patients with advanced ovarian cancer.

Protective effects of primary neural stem cell treatment in ischemic stroke models.

Strokes are a major cause of neurological disability. Stem cell replacement therapy is a potential novel strategy of treating patients that have experienced strokes. The present study examined the protective role of neural stem cell (NSC) administration in oxygen-glucose deprivation (OGD) injury and ischemic stroke animal models. Primary cultured embryonic NSCs and brain microvascular endothelial cells were indirectly co-cultured for in vitro testing. A rat model of embolic middle cerebral artery occlusion (MCAO) was used to assess the morphological and functional changes that occur following treatment with NSCs. The role of the phosphoinositide 3-kinase/protein kinase b/glycogen synthase kinase 3β (PI3K/Akt/GSK-3β) signaling pathway in the neuroprotective effects of NSC treatment was also determined. It was demonstrated in vivo and in vitro that NSC administration may attenuate the brain injury caused by stroke. Furthermore, the results suggest that activation of PI3k/Akt/GSK-3β signaling pathway serves a role in attenuating OGD injury. Inflammation, synaptic remodeling and autophagy may be improved following NSC treatment and behavioral testing suggests that treatment with NSCs improves functional recovery in rats following MCAO.

Concomitant use of mesenchymal stem cells and neural stem cells for treatment of spinal cord injury: A combo cell therapy approach

Treatment: with neural stem cells (NSCs) provides a hope to recover the neural damage and compensate for the lost neural structures for restoration of interrupted neural communications above and below the site of injury. However, cell-based therapy approach suffers from many biological barriers and technical caveats which severely hamper the prognosis. The biochemically-rich microenvironment at the site of spinal cord injury (SCI), the continuing neuro-degenerative process and infiltrating immune cells offer a serious barrier to the donor cells. We hypothesized that mesenchymal stem cells (MSCs) concomitantly delivered with NSCs would significantly enhance the effectiveness of cell-based therapy for SCI. In a rodent model of SCI (n = 15 animals/group), MSCs labeled with PKH67 (green fluorescence dye) were delivered on day1 after SCI whereas the same animals were treated with NSCs during the subacute phase on day3 (group-5). In comparison with untreated control (group-1), sham group (without cell treatment; group-2), MSCs alone (group-3) and NSCs alone treated animals (group-4), the combined cell treated animals (group-5) showed significantly higher homing of cells at the site of injury during in vivo imaging. Caspase-3 activity was lower in group-5 (P < 0.05 vs all groups) with concomitant reduction in the pro-inflammatory cytokines IL-1β and IL-6 (P < 0.05 vs all groups). All cell therapy groups showed significant improvement in neurological function as compared to group-2, however, it was highest in group-5 (P < 0.05 vs all groups). In conclusion, combined treatment with (NSCs + MSCs) enhances NSCs survival and functional recovery in SCI and is superior to the treatment with either of NSCs or MSCs alone.

MiR-7 inhibited peripheral nerve injury repair by affecting neural stem cells migration and proliferation through cdc42.

ObjectiveNeural stem cells play an important role in the recovery and regeneration of peripheral nerve injury, and the microRNA-7 (miR-7) regulates differentiation of neural stem cells. This study aimed to explore the role of miR-7 in neural stem cells homing and proliferation and its influence on peripheral nerve injury repair.MethodsThe mice model of peripheral nerve injury was created by segmental sciatic nerve defect (sciatic nerve injury), and neural stem cells treatment was performed with a gelatin hydrogel conduit containing neural stem cells inserted into the sciatic nerve injury mice. The Sciatic Function Index was used to quantify sciatic nerve functional recovery in the mice. The messenger RNA and protein expression were detected by reverse transcription polymerase chain reaction and Western blot, respectively. Luciferase reporter assay was used to confirm the binding between miR-7 and the 3’UTR of cell division cycle protein 42 (cdc42). The neural stem cells migration and proliferation were analyzed by transwell assay and a Cell-LightTM EdU DNA Cell Proliferation kit, respectively.ResultsNeural stem cells treatment significantly promoted nerve repair in sciatic nerve injury mice. MiR-7 expression was decreased in sciatic nerve injury mice with neural stem cells treatment, and miR-7 mimic transfected into neural stem cells suppressed migration and proliferation, while miR-7 inhibitor promoted migration and proliferation. The expression level and effect of cdc42 on neural stem cells migration and proliferation were opposite to miR-7, and the luciferase reporter assay proved that cdc42 was a target of miR-7. Using co-transfection into neural stem cells, we found pcDNA3.1-cdc42 and si-cdc42 could reverse respectively the role of miR-7 mimic and miR-7 inhibitor on neural stem cells migration and proliferation. In addition, miR-7 mimic-transfected neural stem cells could abolish the protective role of neural stem cells on peripheral nerve injury.ConclusionMiR-7 inhibited peripheral nerve injury repair by affecting neural stem cells migration and proliferation through cdc42.

Transplantation of autologous neural stem cells for treatment of Parkinson's disease: study protocol for a non-randomized controlled trial

Background and objectives: As degenerative changes in dopaminergic neurons occur only in the substantia nigra and striatum of patients with Parkinson's disease (PD), cellular therapy is suitable for this condition. However, previous clinical studies using stem cells for treatment of PD have short follow-ups. Thus, studies with longer follow-ups are required to further investigate the efficacy of stem cell-based therapy. Design: A non-randomized controlled trial. Methods: Ninety eligible PD patients will be recruited from the Department of Neurology at the Affiliated Hospital of Xuzhou Medical University, China. These patients will be assigned to three groups according to each patient's or their legal guardians’ wishes (n = 30 per group). In the control group, 12-week routine drug treatment will be performed. In intrathecal administration and intravenous administration groups, intrathecal administration of autologous neural stem cells (NSCs) into the subarachnoid space or intravenous administration of autologous NSCs will be performed once a week for 4 successive weeks in addition to the 12-week routine drug treatment. Outcome measures: The primary outcome measure is symptom improvement rate at 36 months post-treatment. Secondary outcome measures are nigrostriatal dopamine content, α-synuclein content in blood and cerebrospinal fluid, Barthel index, and safety indicators. Discussion: This study will be performed to demonstrate efficacy of autologous NSC transplantation as a prospective treatment for PD and investigate differences between intrathecal and intravenous transplantation routes, thus providing objective quantitative evidence for clinical applications. Ethics and dissemination: This study was designed in July 2017. Ethics approval from Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University of China was achieved on December 22, 2017 (approval No. XYFY2017-KL052-01). The study protocol was registered on December 25, 2017. Patient recruitment began in January 2018 and will end in January 2019. Each patient will be followed up for 36 months. Follow-ups will be completed in January 2022. Data analysis will be performed in July 2022. Results will be disseminated by publication in a peer-reviewed journal. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-ONC-17014141). Protocol version (1.0).

Neural Stem Cells Expressing bFGF Reduce Brain Damage and Restore Sensorimotor Function after Neonatal Hypoxia-Ischemia

Background/Aims: Neonatal hypoxia-ischemia (HI) causes severe brain damage and significantly increases neonatal morbidity and mortality. Increasing evidences have verified that stem cell-based therapy has the potential to rescue the ischemic tissue and restore function via secreting growth factors after HI. Here, we had investigated whether intranasal neural stem cells (NSCs) treatment improves the recovery of neonatal HI, and NSCs overexpressing basic fibroblast growth factor (bFGF) has a better therapeutic effect for recovery than NSCs treatment only. Methods: We performed permanent occlusion of the right common carotid artery in 9-day old ICR mice as animal model of neonatal hypoxia-ischemia. At 3 days post-HI, NSC, NSC-GFP, NSC-bFGF and vehicle were delivered intranasally. To determine the effect of intranasal NSC, NSC-GFP and NSC-bFGF treatment on recovery after HI, we analyzed brain damage, sensor-motor function and cell differentiation. Results: It was observed that intranasal NSC, NSC-GFP and NSC-bFGF treatment decreased gray and white matter loss area in comparison with vehicle-treated mouse. NSC, NSC-GFP and NSC-bFGF treatment also significantly improved sensor motor function in cylinder rearing test and adhesive removal test, however, NSC-bFGF-treatment was more effective than NSC-treatment in the improvement of somatosensory function. Furthermore, compared with NSC and NSC-GFP, NSC-bFGF treatment group appeared to differentiate into more neurons. Conclusion: Taken together, intranasal administration of NSCs is a promising therapy for treatment of neonatal HI, but NSCs overexpressing bFGF promotes the survival and differentiation of NSCs, and consequently achieves a better therapeutic effect in improving recovery after neonatal HI.

P.1.j.007 - Enhancement of cognitive performance by chronic ethosuximide and neural stem cell treatment in genetic absence epileptic WAG/Rij rats

P.1.j.007 - Enhancement of cognitive performance by chronic ethosuximide and neural stem cell treatment in genetic absence epileptic WAG/Rij rats

Delayed administration of neural stem cells after hypoxia-ischemia reduces sensorimotor deficits, cerebral lesion size, and neuroinflammation in neonatal mice.

Hypoxic-ischemic (HI) encephalopathy causes mortality and severe morbidity in neonates. Treatments with a therapeutic window >6 h are currently not available. Here, we explored whether delayed transplantation of allogenic neural stem cells (NSCs) at 10 d after HI could be a tool to repair HI brain injury and improve behavioral impairments. HI was induced in 9-d-old mice. Animals received NSCs or vehicle intracranially in the hippocampus at 10 d post-HI. Sensorimotor performance was assessed by cylinder rearing test. Lesion size, synaptic integrity, and fate of injected NSCs were determined by immuno-stainings. Neuroinflammation was studied by immuno-stainings of brain sections, primary glial cultures, and TNFα ELISA. NSC transplantation at 10 d post-insult induced long-term improvement of motor performance and synaptic integrity, and reduced lesion size compared to vehicle-treatment. HI-induced neuroinflammation was reduced after NSC treatment, at least partially by factors secreted by NSCs. Injected NSCs migrated toward and localized at the damaged hippocampus. Transplanted NSCs differentiated toward the neuronal lineage and formed a niche with endogenous precursors. Our study provides evidence of the efficacy of NSC transplantation late after HI as a tool to reduce neonatal HI brain injury through regeneration of the lesion.

Neural Stem Cells Restore Hair Growth Through Activation of the Hair Follicle Niche.

Several types of hair loss result from the inability of hair follicles to initiate the anagen phase of the hair regeneration cycle. Modulating signaling pathways in the hair follicle niche can stimulate entry into the anagen phase. Despite much effort, stem cell-based or pharmacological therapies to activate the hair follicle niche have not been successful. Here, we set out to test the effect of neural stem cell (NSC) extract on the hair follicle niche for hair regrowth. NSC extracts were applied to the immortalized cell lines HaCaT keratinocytes and dermal papilla cells (DPCs) and the shaven dorsal skin of mice. Treatment with NSC extract dramatically improved the growth of HaCaT keratinocytes and DPCs. In addition, NSC extract enhanced the hair growth of the shaven dorsal skin of mice. In order to determine the molecular signaling pathways regulated by NSCs, we evaluated the expression levels of multiple growth and signaling factors, such as insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and bone morphogenetic protein (BMP) family members. We found that treatment with an NSC extract enhanced hair growth by activating hair follicle niches via coregulation of TGF-β and BMP signaling pathways in the telogen phase. We also observed activation and differentiation of intrafollicular hair follicle stem cells, matrix cells, and extrafollicular DPCs in vivo and in vitro. We tested whether activation of growth factor pathways is a major effect of NSC treatment on hair growth by applying the growth factors to mouse skin. Combined growth factors, including TGF-β, significantly increased the hair shaft length and growth rate. DNA damage and cell death were not observed in skin cells of mice treated with the NSC extract for a prolonged period. Overall, our data demonstrate that NSC extract provides an effective approach for promoting hair growth by directly regulating hair follicle niches through TGF-β and BMP signaling pathways as well as induction of core growth factors.

Abstract 129: Optogenetic Inhibition of Striatal Neurons Improves the Survival of Implanted Neural Stem Cell and Neurological Outcomes After Ischemic Stroke

Background: Administration of neural stem cell (NSC) into peri-infarct region is a promising treatment to improve the outcome after brain ischemia. However, whether the survival of implanted NSC is influenced by endogenous neuronal activity remains unclear. Using optogenetic technique, we regulated the activity of striatal neuron and investigated whether the excitation or the inhibition of striatal neuronal activity could improve NSC survival and overall neurological outcome. Methods: Adeno-assosiated virus carrying ChR2 or ArchT gene under the control of promoter CaMKII was injected into mice striatum two weeks before the surgery of 60 minutes transient middle cerebral artery occlusion (tMCAO). NSCs cultured from transgenic mice expressing fluorescent protein or isometric phosphate buffer saline was transplanted into peri-infarct region at striatum at 4 days after tMCAO. The striatal neurons were stimulated 15 minutes daily by 473nm pulse or 530nm constant laser via implanted optical fiber from 7 to 13 days after tMCAO. Neurological severity score (NSS) was assessed at 3 and 14 days. After sacrificing the animals at 14 days after tMCAO, brain infarct volume was measured with cresyl violet staining. The fluorescence intensity and the diffuse area of implanted NSC were calculated to evaluate the survival of NSC. Results: Mice received NSC transplantation and optogenetic inhibition showed smaller infarct volume compared to that only received NSC transplantation or PBS (p&lt;0.05). The fluorescence diffuse area of transplanted NSC was larger in mice with optogenetic inhibition than that without optogenetic inhibition (p&lt;0.05). Mice received NSC transplantation and optogenetic excitation had larger infarct volume and higher NSS than mice only received NSC transplantation (p&lt;0.05), but showed no differences compared to mice received PBS (p&gt;0.05). The fluorescence diffuse area and the mean optical density of transplanted NSC was smaller in mice with optogenetic excitation than that without optogenetic excitation (p&lt;0.05). Conclusion: Inhibition of striatal neuronal activity at sub-acute phase after ischemia can improve the treatment of implanted NSC. To the opposite, excitation of striatal neuronal activity can reduce the NSC treatment.

Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer's disease.

Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimer's disease (AD). A number of studies have reported that inflammatory processes are highly correlated with cognitive deficits in AD-like mice. Transplantation of neural stem cells (NSCs) has been considered as a potential new therapy for the treatment of AD because of its effects in improving cognitive ability. However, NSCs have not been evaluated for their protective effects against inflammatory changes in AD. Here, we injected NSCs into amyloid precursor protein (APP)/PS1 transgenic mice to analyse cognitive function and to measure glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule-1 (Iba-1) and toll-like receptors 4(TLR4) activation. We also quantified TLR-4 pathway-related agents, Aβ concentration and the levels of proinflammatory mediators. Our results showed that in NSC-injected APP/PS1 mice, activation of GFAP, Iba-1, TLR4 and TLR4 pathway-related agents (MyD88, TRIF, P38 MAPK and NF-κB P65) were significantly decreased with decreased expression of proinflammatory mediators (IL-1, IL-6, TNF-α and PGE2). These changes were associated with the amelioration of cognitive deficits, but no difference was found in Aβ concentration. Our results provide novel evidence that NSC transplantation in APP/PS1 mice significantly improved cognitive deficits and was accompanied by the attenuation of inflammatory injury via suppression of glial and TLR4-mediated inflammatory pathway activation. Our data indicate that these pathways may potentially be important therapeutic targets to prevent or delay AD. This study investigated the neuroprotective effect of neural stem cell (NSC) transplantation against Alzheimer's disease (AD) inflammation. We found that NSC treatment in APP/PS1 mice significantly improved cognitive deficits and was accompanied by the attenuation of inflammatory injury via suppression of glial and toll-like receptor 4 (TLR4) activation and its downstream signalling pathways. Our findings indicate that these pathways may be potentially important therapeutic targets to prevent or delay AD.