Restorative effects and mechanisms of neural stem cell transplantation on ischemic brain injury based on the Wnt signaling pathway.

OBJECTIVE: To explore the restorative effects and mechanisms of neural stem cell (NSC) transplantation on ischemic brain injury based on the Wnt signaling pathway. METHODS: Out of 102 male KM mice, 15 were randomly selected as the control group without any intervention, while the remaining 87 underwent middle cerebral artery occlusion (MCAO) using the Zea-Longa suture method. Seven mice that did not successfully model MCAO were excluded, leaving 80 mice that successfully underwent MCAO, randomized into two groups: the Ischemic Brain Injury group (n = 40) receiving 10 µL of sterile PBS solution injected into the lateral ventricle, and the Ischemic Brain Injury + NSCs Transplantation group (n = 40) receiving 10 µL of NSCs suspension injected into the lateral ventricle. RESULTS: Compared to the ischemic brain injury group, mice in the Ischemic Brain Injury + NSCs Transplantation group exhibited significantly alleviated edema in the middle cerebral artery supply area, with neurons displaying more normal morphological characteristics and fewer signs of degeneration and necrosis. The mice with NSC transplantation had significantly smaller infarct volume than those in the ischemic brain injury group (p < 0.05). The mice with NSC transplantation showed significantly lower Zea-Longa scores and a lower proportion of TUNEL-positive cells compared to those in the ischemic brain injury group (p < 0.05). CONCLUSION: NSC transplantation can significantly inhibit neuronal apoptosis in the ischemic region of mice with ischemic brain injury, alleviate brain tissue edema, reduce infarct volume, and improve neurological function. The mechanism may be related to Wnt signaling pathway activation.

Spatial normalization and quantification approaches of PET imaging for neurological disorders.

Quantification approaches of positron emission tomography (PET) imaging provide user-independent evaluation of pathophysiological processes in living brains, which have been strongly recommended in clinical diagnosis of neurological disorders. Most PET quantification approaches depend on spatial normalization of PET images to brain template; however, the spatial normalization and quantification approaches have not been comprehensively reviewed. In this review, we introduced and compared PET template-based and magnetic resonance imaging (MRI)-aided spatial normalization approaches. Tracer-specific and age-specific PET brain templates were surveyed between 1999 and 2021 for 18F-FDG, 11C-PIB, 18F-Florbetapir, 18F-THK5317, and etc., as well as adaptive PET template methods. Spatial normalization-based PET quantification approaches were reviewed, including region-of-interest (ROI)-based and voxel-wise quantitative methods. Spatial normalization-based ROI segmentation approaches were introduced, including manual delineation on template, atlas-based segmentation, and multi-atlas approach. Voxel-wise quantification approaches were reviewed, including voxel-wise statistics and principal component analysis. Certain concerns and representative examples of clinical applications were provided for both ROI-based and voxel-wise quantification approaches. At last, a recipe for PET spatial normalization and quantification approaches was concluded to improve diagnosis accuracy of neurological disorders in clinical practice.

Atypical extraventricular neurocytoma: A case report.

Atypical extraventricular neurocytoma (EVN) is a rare condition characterized by diffuse tumor cell hyperplasia, increased neovascularization, increased necrosis, and aggressive characteristics. A case of a 25-year old man who presented with atypical EVN in his left parietal - occipital flaps is reported. Magnetic resonance imaging (MRI) revealed a well-defined globular mass with heterogeneous signals in the left parietal lobe, and mild perilesional edema. After left parietal craniotomy and tumor excision, pathologic examination of the resected tissue revealed that the lesion was localized mainly in the white matter and imbued with tumor cells possessing round hyperchromatic nuclei with perinuclear halos and increased microvascular proliferation. The patient underwent radiotherapy at 21st postoperative day. Over the past 26 months, the patient has been regularly followed up, and so far no neurologic deficits have been observed. The latest MRI showed that the tumor bed was stable with slight peritumoral edema. The results of clinical, histopathological and immunohistochemical examinations indicate that atypical EVN is a rare neoplasm with unique radiographic and pathologic characteristics. It possesses more aggressive properties than typical EVN.

Hypoxia-associated circDENND2A promotes glioma aggressiveness by sponging miR-625-5p.

BACKGROUND: As a newfound type of non-coding RNA, circular RNAs (circRNAs) are involved in various physiological and pathological processes via regulation of gene expression. Increasing evidence shows that aberrantly expressed circRNAs play a crucial role in the initiation and progression of many tumors. However, the functions of different circRNAs in gliomas remain elusive. METHODS: The levels of circRNAs, miRNAs, and mRNAs were quantified by qPCR. The interaction between circDENND2A and miR-625-5p was determined by luciferase reporter and pull-down assays. The migratory and invasive capabilities of glioma cells were examined by wound healing and Transwell assays. Immunohistochemistry was performed to analyze the HIF1α level in glioma tissues. RESULTS: We predicted circDENND2A (has_circ_0002142) to be a hypoxia-responsive circRNA in glioma via a bioinformatic analysis. We found that hypoxia induced the expression of circDENND2A, which promoted migration and invasion of glioma cells. To understand the behaviors of circDENND2A in glioma, we studied the putative miRNAs targeted by circDENND2A and identified circDENND2A as an efficient sponge of miR-625-5p in glioma cells. Phenotype experiments verified that circDENND2A was required for the hypoxia-induced migration and invasion of glioma cells and that this occurred by sponging of miR-625-5p. Notably, glioma tissues overexpressing HIF1α exhibited a high expression of circDENND2A as well as a low expression of miR-625-5p. circDENND2A was negatively correlated with miR-625-5p. CONCLUSION: circDENND2A is required for the hypoxia-induced malignancy of glioma cells and functions by sponging miR-625-5p.

DL-3-n-butylphthalide promotes dendrite development in cortical neurons subjected to oxygen-glucose deprivation/reperfusion.

The limited degree of functional recovery is closely associated with the condition of the periinfarct cortex after ischemic stroke. The model of oxygen-glucose deprivation in cultured neurons could partly simulate this condition. Proper dendritic morphology is crucial for the correct wiring of neuronal function. Hence, the question of how to facilitate the plasticity of neural dendrites is of great significance. DL-3-n-butylphthalide is an efficient medication for ischemic stroke. In this study, in addition to having neuroprotective effects, DL-3-n-butylphthalide could increase the number of primary and secondary dendrites and of dendritic tips as confirmed by Sholl analysis. This study further demonstrated that DL-NBP inactivates PI3K/AKT signaling to positively regulate dendritic branching.

Fucoxanthin Activates Apoptosis via Inhibition of PI3K/Akt/mTOR Pathway and Suppresses Invasion and Migration by Restriction of p38-MMP-2/9 Pathway in Human Glioblastoma Cells.

Fucoxanthin is rich in seaweed and considered as effective anti-cancer drug because of powerful antioxidant properties. The objective of this study was to investigate the role of fucoxanthin on apoptosis, invasion and migration of glioma cells. Firstly, fucoxanthin showed obvious cytotoxicity against human glioma cancer cell line U87 and U251, however, there was no inhibitory effect on normal neuron. And then, fucoxanthin induced apoptotic cell death showed by the condensation of chromatin material stained with Hoechest 33342, and reduced mitochondrial membrane potential via DIOC6(3) staining, and enhanced apoptosis by annexin V-FITC/SYTOX Green double staining on U87 and U251 cell lines. Transmission electron microscopy and western blotting were used to determine ultrastructure of U87 cell and expression of proteins related to apoptosis. A scratch wound healing assay and the expression of matrix metalloproteinases (MMPs), and a tans-well assay were used to investigate cell migration and invasion, respectively. Additionally, we uncovered upstream signaling Akt/mTOR and p38 pathways induced by incubation U87 and U251 cell lines with fucoxanthin that mediated cell apoptosis, migration and invasion by using PI3K and p38 inhibitors. Moreover, incubation of fucoxanthin obviously reduced the weight and volume of glioma mass of U87 cells in nude mice. Furthermore, we also examined the glioma mass of U87 cells by hematoxylin-eosin staining, TUNEL assay and western blot, and these outcomes in vivo consistently confirmed that above results in vitro. Taken together, these findings suggest that fucoxanthin augments apoptosis, and reduces cell proliferation, migration and invasion, and reveals a potential mechanism of fucoxanthin-mediated Akt/mTOR and p38 susspression in human glioblastoma cell line.

Quantitative research into the deconditioning of hemodynamic to disorder of consciousness carried out using transcranial Doppler ultrasonography and photoplethysmography obtained via finger-transmissive absorption.

In this study, transcranial Doppler ultrasonography (TCD) and photoplethysmography (PPG) have been utilized, through the observation of peripheral and cerebrovascular hemodynamic changes of the disorder of consciousness (DOC) patients, measured on clinical behavior scale of Coma Recovery Score-Revised (CRS-R) to obesrve their diagnostic value in evaluation of DOC patients. TCD ultrasound was used to evaluate the flow velocity and waveform patterns of middle cerebral artery (MCA), while PPG infrared signals were utilized to assess the peripheral circulation as a mean of measuring cardiovascular activities. The research was carried out on a sample of 36 individuals, of which 16 met the DOC criteria and 20 were healthy individuals. Each person in the patients groups was assessed by the CRS-R. The velocity of middle cerebral artery in tested patients in a whole cardiac cycle, detected by TCD, decreased comparing with normal values. The values of pulsatility index (PI) of the MCA increased in patients groups comparing with normal. Through binary variables correlation analysis, we found that the PI of the left MCA of TCD of the patients significantly inversely correlated with their motor subscore, included in their CRS-R in the level of α = 0.05 (Pearson's product-moment correlation coefficient = -0.556, p = 0.025). The values of photoplethysmographic augmentation index (PAI) that were detected by PPG increased comparing with normal. Finally, using binary variables correlation analysis we found the significant inverse correlation between the PAI of PPG and the mean velocity of the left MCA of the TCD in the level of α = 0.05 (Pearson's product-moment correlation coefficient = -0.377, p = 0.022) in all the groups. The results of this study revealed a specific relationship between PI and PAI in the DOC patients. That relationship can potentially be exploited to enhance the capabilities in early assessment of the deconditioning of the DOC patients' cardiovascular system and its influence on their cerebral vascular system. Ultimately, the dependency discovered can assist in predicting the tendency of the prognosis of the DOC patients in clinic.

Quercetin promotes neuronal and behavioral recovery by suppressing inflammatory response and apoptosis in a rat model of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a common and devastating disease affecting millions of people worldwide annually. Exaggerated inflammation and apoptosis are two pivotal pathological processes for secondary brain injury after ICH. Quercetin, a flavonoid widely distributed in various herbs, fruits and vegetables, has been proved to improve neuronal functional recovery in spinal cord injury rats. However, the efficacy of quercetin in caring for post-ICH brain injury has not been investigated. In the present study, we established an ICH model by injecting type VII bacterial collagenase (0.5U) into the central striatum of male Sprague-Dawley rats. The animals were randomized to four groups: sham-operation group; ICH + vehicle group; ICH + 5 mg/kg quercetin group; and ICH + 50 mg/kg quercetin group. The expression levels of IL-1ß, IL-4, IL-6 and TNF-α in the brain tissue were assayed by Real-time PCR, ELISA and Western Blot, and cell apoptosis was assayed by TUNEL and caspase-3 staining 3 days after model establishment. It was found that the lesion volume, the brain water content, the expression levels of the four inflammation markers and the number of apoptotic cells were reduced significantly in ICH rats receiving quercetin, especially in 50 mg/kg quercetin group. These results confirmed the therapeutic efficacy of quercetin in repairing brain injury, probably by inhibiting inflammatory response and apoptosis, thus promoting nerve functional restoration.

Hyperactive external awareness against hypoactive internal awareness in disorders of consciousness using resting-state functional MRI: highlighting the involvement of visuo-motor modulation.

Resting-state functional MRI (fMRI) has emerged as a valuable tool to characterize the complex states encompassing disorders of consciousness (DOC). Awareness appears to comprise two coexistent, anticorrelated components named the external and internal awareness networks. The present study hypothesizes that DOC interrupts the balance between the internal and external awareness networks. To gain more understanding of this phenomenon, the present study analyzed resting-state fMRI data from 12 patients with DOC versus 12 healthy age-matched controls. The data were explored using independent component analysis and amplitude of low-frequency fluctuation (ALFF) analysis. The results indicated that DOC deactivated midline areas associated with internal awareness. In addition, external awareness was strengthened in DOC because of increased activation in the insula, lingual gyrus, paracentral and supplementary motor area. The activity patterns suggested strengthened external awareness against weakened internal awareness in DOC. In particular, increased activity found in the insula, lingual gyrus, paracentral and supplementary motor area of patients with DOC implied possible involvement of augmented visuo-motor modulation in these patients. DOC is probably related to hyperactive external awareness opposing hypoactive internal awareness. This unique pattern of brain activity may potentially be a prognostic marker for DOC.

Ligand-mediated endocytosis of nanoparticles in neural stem cells: implications for cellular magnetic resonance imaging.

Neural stem cells (NSCs) have great prospects in therapy for neurological disorders. However, the correlation between improved function and stem cell transplantation has not been fully elucidated. A non-invasive method for stem cell tracking is crucial for clinical studies. In the present study, NSCs were infected with lentiviral vectors, and the expression of transferrin receptor (TfR) in neural stem cells after lentivirus transfection (TfR-NSC) was confirmed by western blot analysis. TfR-NSCs were incubated with 1.8 nM ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) or transferrin (Tf)-conjugate of USPIO nanoparticles (Tf-USPIOs). Tf-USPIO enhanced the cellular iron content in TfR-NSCs 80 ± 18 % compared to USPIOs. These results demonstrated that TfR overexpressed in neural stem cells specifically internalized Tf-USPIOs. Furthermore, the results indicate that TfR reporter imaging may be a valuable way to evaluate the efficacy of neural stem cell treatment.

Efficacy of microsurgery for congenital neural tube defects in newborns.

OBJECTIVE: The purpose of this study was to investigate the clinical value of microsurgery in the treatment of congenital neural tube defect (CNTD) in newborns. METHODS: Eighty-five CNTD newborns withlipomyelomeningocele admitted to our hospital from March 2016 to December 2018 were retrospectively selected as study subjects. They were divided into a study group (SG, 43 cases, that received meningocele repair combined with tethered cord release within 6 h to 30 d after birth) and the control group (CG, 42 cases, that received meningocele repair combined with tethered cord release past 30 d after birth) according to the treatment regimen. Newborns in both groups were evaluated for short-term and long-term outcome of the surgery and the degree of postoperative untethering, and both groups were followed up dynamically to record changes in gross motor function and quality of life and assess risk factors. RESULTS: In terms of short-term outcomes, the total effective rate was 93.02% in SG and 85.71% in CG (P > 0.05); in terms of the long-term outcomes, the total effective rate was 88.37% in SG and 69.05% in CG (P < 0.05). The postoperative release of the newborns was evaluated according to the Kirollos grading system, which showed that SG had 40 (93.02%) cases of grade 1 untethering, 3 (6.98%) cases of grade 2 untethering, and 0 case of grade 3 untethering, and CG had 30 (71.43%) cases of grade 1 untethering, and 12 (28.57%) cases of grade 2 untethering. At 6 months postoperatively, there were no significant differences in gross motor function and quality of life scores between the two groups (P > 0.05), but at 1 year, 3 years and 4 years postoperatively, the gross motor function and quality of life scores of newborns in the SG were significantly higher than those in the CG (P < 0.05). Multivariate logistic regression analysis showed that age > 1 month was an independent risk factor for surgical outcome (P < 0.05). CONCLUSION: Microsurgery has better short-term and long-term outcomes for newborns with CNTD, and the newborns showed an improvement in the long-term postoperative motor function and quality of life.

Clinical practice guidelines for the management of adult diffuse gliomas.

To follow the revision of the fourth edition of WHO classification and the recent progress on the management of diffuse gliomas, the joint guideline committee of Chinese Glioma Cooperative Group (CGCG), Society for Neuro-Oncology of China (SNO-China) and Chinese Brain Cancer Association (CBCA) updated the clinical practice guideline. It provides recommendations for diagnostic and management decisions, and for limiting unnecessary treatments and cost. The recommendations focus on molecular and pathological diagnostics, and the main treatment modalities of surgery, radiotherapy, and chemotherapy. In this guideline, we also integrated the results of some clinical trials of immune therapies and target therapies, which we think are ongoing future directions. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China and other countries.

First Human Trial of Stem Cell Transplantation in Complex Arrays for Stroke Patients Using the Intracerebral Microinjection Instrument.

BACKGROUND: In preclinical studies, the Intracerebral Microinjection Instrument (IMI) has demonstrated the ability to deliver therapeutics within the brain in 3-dimensional arrays from a single overlying penetration while incurring minimal localized trauma. OBJECTIVE: To evaluate the safety and performance of the IMI in its first use in humans to deliver stem cells in complex configurations within brain regions affected by ischemic injury. METHODS: As part of a phase 1 study, 3 chronically hemiparetic motor stroke patients received intracerebral grafts of the therapeutic stem cell line, NSI-566, using the IMI and its supporting surgical planning software. The patients were 37 to 54 yr old, had ischemic strokes more than 1 yr prior to transplantation, and received Fugl-Meyer motor scale scores of 17-48 at screening. During a single surgical procedure, patients received several neural grafts (42 ± 3) within the peri-infarct region targeted strategically to facilitate neural repair. RESULTS: The IMI enabled multiple cellular deposits to be safely placed peripheral to stroke lesions. The procedure was well tolerated, recovery was uneventful, and there occurred no subsequent complications. The IMI performed reliably throughout the procedures without evident targeting errors. One year after transplantation, all 3 subjects displayed significant clinical improvement, and imaging analysis demonstrated occupation of infarct cavities with new tissue without tumor formation. CONCLUSION: IMI technology permits unprecedented numbers of injections to be tactically placed in 3-dimensional arrays safely and reliably in human subjects.This advanced methodology can optimize the benefits of novel therapeutics by enabling versatile 3-dimensional intracerebral targeting.

Effects of Long-Lasting High-Definition Transcranial Direct Current Stimulation in Chronic Disorders of Consciousness: A Pilot Study.

Transcranial direct current stimulation (tDCS) recently was shown to benefit rehabilitation of patients with disorders of consciousness (DOC). However, high-Definition tDCS (HD-tDCS) has not been applied in DOC. In this study, we tried to use HD-tDCS protocol (2 mA, 20 min, the precuneus, and sustaining 14 days) to rehabilitate 11 patients with DOC. Electroencephalography (EEG) and Coma Recovery Scale-Revised (CRS-R) scores were recorded at before (T0), after a single session (T1), after 7 days' (T2), and 14 days' HD-tDCS (T3) to assess the modulation effects. EEG coherence was measured to evaluate functional connectivity during the experiment. It showed that 9 patients' scores increased compared with the baseline. The central-parietal coherence significantly decreased in the delta band in patients with DOC. EEG coherence might be useful for assessing the effect of HD-tDCS in patients with DOC. Long-lasting HD-tDCS over the precuneus is promising for the treatment of patients with DOC.

Stable Intracerebral Transplantation of Neural Stem Cells for the Treatment of Paralysis Due to Ischemic Stroke.

NSI-566 is a stable, primary adherent neural stem cell line derived from a single human fetal spinal cord and expanded epigenetically with no genetic modification. This cell line is being tested in clinical trials in the U.S. for treatment of amyotrophic lateral sclerosis and spinal cord injury. In a single-site, phase I study, we evaluated the feasibility and safety of NSI-566 transplantation for the treatment of hemiparesis due to chronic motor stroke and determined the maximum tolerated dose for future trials. Three cohorts (n = 3 per cohort) were transplanted with one-time intracerebral injections of 1.2 × 107 , 2.4 × 107 , or 7.2 × 107 cells. Immunosuppression therapy with tacrolimus was maintained for 28 days. All subjects had sustained chronic motor strokes, verified by magnetic resonance imaging (MRI), initiated between 5 and 24 months prior to surgery with modified Rankin Scores [MRSs] of 2, 3, or 4 and Fugl-Meyer Motor Scores of 55 or less. At the 12-month visit, the mean Fugl-Meyer Motor Score (FMMS, total score of 100) for the nine participants showed 16 points of improvement (p = .0078), the mean MRS showed 0.8 points of improvement (p = .031), and the mean National Institutes of Health Stroke Scale showed 3.1 points of improvement (p = .020). For six participants who were followed up for 24 months, these mean changes remained stable. The treatment was well tolerated at all doses. Longitudinal MRI studies showed evidence indicating cavity-filling by new neural tissue formation in all nine patients. Although this was a small, one-arm study of feasibility, the results are encouraging to warrant further studies. Stem Cells Translational Medicine 2019;8:999-1007.

Nearly asymptomatic intracranial capillary hemangiomas: A case report and literature review.

The present study reported a nearly asymptomatic case of intracranial capillary hemangioma (ICHs), which are rare benign vascular tumors or tumor-like lesions. A 33-year-old female came to the hospital with a complaint of a slight but recurring morning headache concentrated in the left posterior occipital area. These headaches spontaneously resolved without any treatment. Computed tomography and magnetic resonance imaging revealed a mass inside the left occipital lobe. The patient refused to undergo conservative observation at home and insisted on radical therapy. Prior to surgery, an atypical meningioma or astrocytoma was suspected. A navigation-guided brain-mass resection was performed under general anesthesia and a solid mass closely associated with the tentorium cerebelli was completely resected. Histopathological analysis confirmed diagnosis of an ICH. The patient recovered well and experienced no major neurological defects, apart from an issue with the right visual field. The present study also conducted a retrospective literature review of papers published in English describing cases of intracranial capillary hemangiomas. A PubMed search identified 19 articles comprising 29 cases. The clinical symptoms of ICH are diverse and all reported cases in the literature were symptomatic. Previous studies demonstrated that diagnoses of intracranial capillary hemangioma are usually made during surgical resection by histopathological examination. Treatment for ICH remains empirical and surgery is the most common method of treatment. Patient prognosis is generally good-the majority of patients achieve long-term, event- and progression-free survival.

Endoscopic biopsy of a B-cell lymphoma involving the entire ventricular system: A case report.

A 62-year-old male suffering from vomiting and mild preceding nausea for 15 days was examined in the present case report. Magnetic resonance imaging revealed a homogeneously enhancing cluster-like lesion involving the lateral, third and fourth ventricles. An endoscopic biopsy was performed, and histopathological examination led to the diagnosis of a high-grade diffuse large B-cell lymphoma. To the best of our knowledge, the present study reports the first case of a primary lymphoma involving the entire ventricular system. Therefore, primary lymphomas should be considered in the list of ventricular tumors. An endoscopic biopsy requires minimal invasion to obtain an adequate tissue sample, and frequently leads to the correct diagnosis and subsequent treatment protocols.

CGCG clinical practice guidelines for the management of adult diffuse gliomas.

The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas provided recommendations for diagnostic and therapeutic procedures. The Panel covered all fields of expertise in neuro-oncology, i.e. neurosurgeons, neurologists, neuropathologists, neuroradiologists, radiation and medical oncologists and clinical trial experts. The task made clearer and more transparent choices about outcomes considered most relevant through searching the references considered most relevant and evaluating their value. The scientific evidence of papers collected from the literature was evaluated and graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and recommendations were given accordingly. The recommendations will provide a framework and assurance for the strategy of diagnostic and therapeutic measures to reduce complications from unnecessary treatment and cost. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China.

Pcdh11x Negatively Regulates Dendritic Branching.

Proper formation of neuronal dendritic branching is crucial for correct brain function. The number and distribution of receptive synaptic contacts are defined by the size and shape of dendritic arbors. Our previous research found that protocadherin 11 X-linked protein (Pcdh11x) is predominantly expressed in neurons and has an influence on dendritic branching. In this study, gain-of-function and loss-of-function experiments revealed that Pcdh11x acts as a negative regulator of dendritic branching in cultured cortical neurons derived from embryonic day 16 mice. Overexpression of wild-type Pcdh11x (Pcdh11x-GFP) reduced dendritic complexity, whereas knockdown of Pcdh11x increased dendritic branching. It was further demonstrated that Pcdh11x activates PI3K/AKT signaling to negatively regulate dendritic branching.

Transplanted hUCB-MSCs migrated to the damaged area by SDF-1/CXCR4 signaling to promote functional recovery after traumatic brain injury in rats.

Transplanted human umbilical cord mesenchymal stem cells (hUC-MSCs) have exhibited considerable therapeutic potential for traumatic brain injury (TBI). However, how hUC-MSCs migrating to the injury region and the mechanism of hUC-MSCs promoting functional recovery after TBI are still unclear. In this study, we investigated whether stromal cell-derived factor-1 (SDF-1) was involved in the hUC-MSCs migration and the possible mechanisms that might be involved in the beneficial effect on functional recovery. In vitro experiments demonstrated that SDF-1 induces a concentration-dependent migration of hUC-MSCs. Furthermore, pre-treatment with the CXCR4-specific antagonist AMD3100 significantly prevented the migration of hUC-MSCs in vitro. We found that the expression of SDF-1 increased significantly around the damaged area. Transplanted hUC-MSCs were localized to regions where SDF-1 was highly expressed. Additionally, our results showed that hUC-MSCs-treated animals showed significantly improved functional recovery compared with controls. In hUC-MSCs-transplanted group, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells were decreased and BrdU-positive cells were significantly increased compared with control group, more of BrdU-positive cells co-localized with GFAP. These suggest that SDF-1 plays an important role in the migration of hUC-MSCs to the damaged area and hUC-MSCs are beneficial for functional recovery after TBI.