Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Robust and Multifunctional Nanoparticles Assembled from Natural Polyphenols and Metformin for Efficient Spinal Cord Regeneration.

The treatment of spinal cord injury (SCI) remains unsatisfactory owing to the complex pathophysiological microenvironments at the injury site and the limited regenerative potential of the central nervous system. Metformin has been proven in clinical and animal experiments to repair damaged structures and functions by promoting endogenous neurogenesis. However, in the early stage of acute SCI, the adverse pathophysiological microenvironment of the injury sites, such as reactive oxygen species and inflammatory factor storm, can prevent the activation of endogenous neural stem cells (NSCs) and the differentiation of NSCs into neurons, decreasing the whole repair effect. To address those issues, a series of robust and multifunctional natural polyphenol-metformin nanoparticles (polyphenol-Met NPs) were fabricated with pH-responsiveness and excellent antioxidative capacities. The resulting NPs possessed several favorable advantages: First, the NPs were composed of active ingredients with different biological properties, without the need for carriers; second, the pH-responsiveness feature could allow targeted drug delivery at the injured site; more importantly, NPs enabled drugs with different performances to exhibit strong synergistic effects. The results demonstrated that the improved microenvironment by natural polyphenols boosted the differentiation of activated NSCs into neurons and oligodendrocytes, which could efficiently repair the injured nerve structures and enhance the functional recovery of the SCI rats. This work highlighted the design and fabrication of robust and multifunctional NPs for SCI treatment via efficient microenvironmental regulation and targeted NSCs activation.

Effects of Univariate Stiffness and Degradation of DNA Hydrogels on the Transcriptomics of Neural Progenitor Cells.

Mechanical interactions between cells and extracellular matrix (ECM) are critical for stem cell fate decision. Synthetic models of ECM, such as hydrogels, can be used to precisely manipulate the mechanical properties of the cell niche and investigate how mechanical signals regulate the cell behavior. However, it has long been a great challenge to tune solely the ECM-mimic hydrogels' mechanical signals since altering the mechanical properties of most materials is usually accompanied by chemical and topological changes. Here, we employ DNA and its enantiomers to prepare a series of hydrogels with univariate stiffness regulation, which enables a precise interpretation of the fate decision of neural progenitor cells (NPCs) in a three-dimensional environment. Using single-cell RNA sequencing techniques, Monocle pseudotime trajectory and CellphoneDB analysis, we demonstrate that the stiffness of the hydrogel alone does not influence the differentiation of NPCs, but the degradation of the hydrogel that enhances cell-cell interactions is possibly the main reason. We also find that ECM remodeling facilitates cells to sense mechanical stimuli.

Neuroanatomical Localization of Rapid Eye Movement Sleep Behavior Disorder in Human Brain Using Lesion Network Mapping.

OBJECTIVE: To localize the neuroanatomical substrate of rapid eye movement sleep behavior disorder (RBD) and to investigate the neuroanatomical locational relationship between RBD and α-synucleinopathy neurodegenerative diseases. MATERIALS AND METHODS: Using a systematic PubMed search, we identified 19 patients with lesions in different brain regions that caused RBD. First, lesion network mapping was applied to confirm whether the lesion locations causing RBD corresponded to a common brain network. Second, the literature-based RBD lesion network map was validated using neuroimaging findings and locations of brain pathologies at post-mortem in patients with idiopathic RBD (iRBD) who were identified by independent systematic literature search using PubMed. Finally, we assessed the locational relationship between the sites of pathological alterations at the preclinical stage in α-synucleinopathy neurodegenerative diseases and the brain network for RBD. RESULTS: The lesion network mapping showed lesions causing RBD to be localized to a common brain network defined by connectivity to the pons (including the locus coeruleus, dorsal raphe nucleus, central superior nucleus, and ventrolateral periaqueductal gray), regardless of the lesion location. The positive regions in the pons were replicated by the neuroimaging findings in an independent group of patients with iRBD and it coincided with the reported pathological alterations at post-mortem in patients with iRBD. Furthermore, all brain pathological sites at preclinical stages (Braak stages 1-2) in Parkinson's disease (PD) and at brainstem Lewy body disease in dementia with Lewy bodies (DLB) were involved in the brain network identified for RBD. CONCLUSION: The brain network defined by connectivity to positive pons regions might be the regulatory network loop inducing RBD in humans. In addition, our results suggested that the underlying cause of high phenoconversion rate from iRBD to neurodegenerative α-synucleinopathy might be pathological changes in the preclinical stage of α-synucleinopathy located at the regulatory network loop of RBD.

Lesions causing central sleep apnea localize to one common brain network.

Objectives: To characterize the specific brain regions for central sleep apnea (CSA) and identify its functional connectivity network. Methods: We performed a literature search and identified 27 brain injuries causing CSA. We used a recently validated methodology termed "lesion network mapping" to identify the functional brain network subtending the pathophysiology of CSA. Two separate statistical approaches, the two-sample t-test and the Liebermeister test, were used to evaluate the specificity of this network for CSA through a comparison of our results with those of two other neurological syndromes. An additional independent cohort of six CSA cases was used to assess reproducibility. Results: Our results showed that, despite lesions causing CSA being heterogeneous for brain localization, they share a common brain network defined by connectivity to the middle cingulate gyrus and bilateral cerebellar posterior lobes. This CSA-associated connectivity pattern was unique when compared with lesions causing the other two neurological syndromes. The CAS-specific regions were replicated by the additional independent cohort of six CSA cases. Finally, we found that all lesions causing CSA aligned well with the network defined by connectivity to the cingulate gyrus and bilateral cerebellar posterior lobes. Conclusion: Our results suggest that brain injuries responsible for CSA are part of a common brain network defined by connectivity to the middle cingulate gyrus and bilateral cerebellar posterior lobes, lending insight into the neuroanatomical substrate of CSA.

Fornix alterations induce the disruption of default mode network in patients with adamantinomatous craniopharyngiomas.

Adamantinomatous craniopharyngioma (ACPs) are rare embryonic tumors and often involve the hypothalamus. The underlying neural substrate of the hypothalamic involvement (HI)-related cognitive decline in patients with ACP is still unclear. We aimed to combine the multi-modal neuroimaging and histological characteristics of the ACP to explore the potential neural substrate of the HI-related cognitive decline. 45 patients with primary ACPs (invasive, 23; noninvasive, 22) and 52 healthy control subjects (HCs) were admitted to the cross-sectional study. No significant difference in cognitive domains was observed between HCs and patients with noninvasive ACPs (NACP). Patients with invasive ACPs (IACP) showed significantly lower working memory performance (WM, p = 0.002) than patients with NACP. The WM decline was correlated with the disruption of the medial temporal lobe (MTL) subsystem in the default mode network (DMN) (r = 0.45, p = 0.004). The increased radial diffusivity of the fornix, indicating demyelinating process, was correlated with the disruption of the MTL subsystem (r = -0.48, p = 0.002). Our study demonstrated that the fornix alterations link DMN disruption to HI-related cognitive decline in patients with ACPs. ACPs that invade the hypothalamus can provide a natural disease model to investigate the potential neural substrate of HI-related cognitive decline.

Highly Permeable DNA Supramolecular Hydrogel Promotes Neurogenesis and Functional Recovery after Completely Transected Spinal Cord Injury.

Regeneration after severe spinal cord injury cannot occur naturally in mammals. Transplanting stem cells to the injury site is a highly promising method, but it faces many challenges because it relies heavily on the microenvironment provided by both the lesion site and delivery material. Although mechanical properties, biocompatibility, and biodegradability of delivery materials have been extensively explored, their permeability has rarely been recognized. Here, a DNA hydrogel is designed with extremely high permeability to repair a 2 mm spinal cord gap in Sprague-Dawley rats. The rats recover basic hindlimb function with detectable motor-evoked potentials, and a renascent neural network is formed via the proliferation and differentiation of both implanted and endogenous stem cells. The signal at the lesion area is conveyed by, on average, 15 newly formed synapses. This hydrogel system offers great potential in clinical trials. Further, it should be easily adaptable to other tissue regeneration applications.

In Vivo Characterization of Cortical and White Matter Microstructural Pathology in Growth Hormone-Secreting Pituitary Adenoma.

BACKGROUND: The growth hormone (GH) and insulin-like-growth factor 1 (IGF-1) axis has long been recognized for its critical role in brain growth, development. This study was designed to investigate microstructural pathology in the cortex and white matter in growth hormone-secreting pituitary adenoma, which characterized by excessive secretion of GH and IGF-1. METHODS: 29 patients with growth hormone-secreting pituitary adenoma (acromegaly) and 31 patients with non-functional pituitary adenoma as controls were recruited and assessed using neuropsychological test, surface-based morphometry, T1/T2-weighted myelin-sensitive magnetic resonance imaging, neurite orientation dispersion and density imaging, and diffusion tensor imaging. RESULTS: Compared to controls, we found 1) acromegaly had significantly increased cortical thickness throughout the bilateral cortex (pFDR < 0.05). 2) T1/T2-weighted ratio in the cortex were decreased in the bilateral occipital cortex and pre/postcentral central gyri but increased in the bilateral fusiform, insular, and superior temporal gyri in acromegaly (pFDR < 0.05). 3) T1/T2-weighted ratio were decreased in most bundles, and only a few areas showed increases in acromegaly (pFDR < 0.05). 4) Neurite density index (NDI) was significantly lower throughout the cortex and bundles in acromegaly (pTFCE < 0.05). 5) lower fractional anisotropy (FA) and higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in extensive bundles in acromegaly (pTFCE < 0.05). 6) microstructural pathology in the cortex and white matter were associated with neuropsychological dysfunction in acromegaly. CONCLUSIONS: Our findings suggested that long-term persistent and excess serum GH/IGF-1 levels alter the microstructure in the cortex and white matter in acromegaly, which may be responsible for neuropsychological dysfunction.

Predicting the location of the preoptic and anterior hypothalamic region by visualizing the thermoregulatory center on fMRI in craniopharyngioma using cold and warm stimuli.

Hypothalamic nuclei in the preoptic and anterior hypothalamic region (POAH) are critically involved in thermoregulation and neuroendocrine regulation and can be displaced by craniopharyngiomas (CPs). We aimed to locate the POAH by visualizing hypothalamic thermoregulation through task-related functional magnetic resonance imaging (fMRI) to guide hypothalamus protection intraoperatively. Nine adult healthy volunteers (HVs) and thirty-two adult primary CP patients underwent task-related fMRI for POAH localization by warm (60° C) and cold (0° C) cutaneous thermoreceptor stimulation. Approach selection and intraoperative POAH protection were performed based on preoperative POAH localization. In all HVs and patients, significant single positive blood oxygen level-dependent (BOLD) signal changes were located in the POAH. The BOLD activity was significantly greater for cold (P=0.03) and warm (P=0.03) stimuli in patients than in HVs. Gross total resection and near-total resection were achieved in 28 (87.5%) and 4 (12.5%) patients, respectively. New-onset diabetes insipidus and new-onset hypopituitarism occurred in 6 patients (18.8%) and 10 patients (31.3%), respectively. Our findings suggest that cutaneous thermoreceptor stimulation could accurately activate the hypothalamic thermoregulatory center and allow POAH localization through task-related fMRI. Preoperative POAH localization could help neurosurgeons protect hypothalamic function intraoperatively. The CP patients were more sensitive to thermal stimulation.

The Functional Reorganization of Language Network Modules in Glioma Patients: New Insights From Resting State fMRI Study.

BACKGROUND: Prior investigations of language functions have focused on the response profiles of particular brain regions. However, the specialized and static view of language processing does not explain numerous observations of functional recovery following brain surgery. To investigate the dynamic alterations of functional connectivity (FC) within language network (LN) in glioma patients, we explored a new flexible model based on the neuroscientific hypothesis of core-periphery organization in LN. METHODS: Group-level LN mapping was determined from 109 glioma patients and forty-two healthy controls (HCs) using independent component analysis (ICA). FC and mean network connectivity (mNC: l/rFCw, FCb, and FCg) were compared between patients and HCs. Correlations between mNC and tumor volume (TV) were calculated. RESULTS: We identified ten separate LN modules from ICA. Compared to HCs, glioma patients showed a significant reduction in language network functional connectivity (LNFC), with a distinct pattern modulated by tumor position. Left hemisphere gliomas had a broader impact on FC than right hemisphere gliomas, with more reduced edges away from tumor sites (p=0.011). mNC analysis revealed a significant reduction in all indicators of FC except for lFCw in right hemisphere gliomas. These alterations were associated with TV in a double correlative relationship depending on the tumor position across hemispheres. CONCLUSION: Our findings emphasize the importance of considering the modulatory effects of core-periphery mechanisms from a network perspective. Preoperative evaluation of changes in LN caused by gliomas could provide the surgeon a reference to optimize resection while maintaining functional balance.

Contrahemispheric Cortex Predicts Survival and Molecular Markers in Patients With Unilateral High-Grade Gliomas.

Background: Malignant high-grade gliomas are characterized by infiltration and destruction of surrounding brain tissue. Alterations in the contrahemispheric brain structure and their roles that may offer prognostically valuable information have not been investigated in high-grade gliomas. Methods: In total, 153 patients with unilateral glioma (low-grade, n = 77; high-grade, n = 76) and 115 healthy controls (HCs) were recruited and scanned with 3-D T1 imaging. The gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) volume in the contrahemisphere were examined. Partial correlation, logistic regression, and multivariate Cox's regression analyses were performed. Results: The contrahemispheric GM volume (CHGMV) in the high-grade glioma patients was significantly decreased compared to that in the HCs/low-grade gliomas (one-way ANOVA, Bonferroni corrected, p < 0.05). The CHGMV is significantly correlated with the WHO grade (r = -0.22, p < 0.05) and contrast-enhanced volume (r = -0.33, p < 0.01). In the high-grade gliomas, the binary logistic regression revealed that the CHGMV can independently predict isocitrate dehydrogenase 1 (IDH1) and P53 mutations. The survival curves revealed that the patients with a low CHGMV had a shorter overall survival (OS) than the patients with a high CHGMV (p = 0.001). The multivariate Cox's regression analysis showed that a low CHGMV can independently predict unfavorable OS with a hazard ratio of 2.883 (p = 0.035). Conclusions: Volume of the contrahemispheric cortex can be potentially used in clinical practice as an imaging biomarker to predict survival and molecular markers in patients with unilateral high-grade gliomas.

Structural plasticity of the bilateral hippocampus in glioma patients.

This study investigates the structural plasticity and neuronal reaction of the hippocampus in glioma patient pre-surgery. Ninety-nine glioma patients without bilateral hippocampus involvement (low-grade, n=52; high-grade, n=47) and 80 healthy controls with 3D T1 images and resting-fMRI were included. Hippocampal volume and dynamic amplitude of low-frequency fluctuation (dALFF) were analyzed among groups. Relationships between hippocampal volume and clinical characteristics were assessed. We observed remote hippocampal volume increases in low- and high-grade glioma and a greater response of the ipsilateral hippocampus than the contralesional hippocampus. The bilateral hippocampal dALFF was significantly increased in high-grade glioma. Tumor-associated epilepsy and the IDH-1 mutation did not affect hippocampal volume in glioma patients. No significant relationship between hippocampal volume and age was observed in high-grade glioma. The Kaplan-Meier curve and log-rank test revealed that large hippocampal volume was associated with shorter overall survival (OS) compared with small hippocampal volume (p=0.007). Multivariate Cox regression analysis revealed that large hippocampal volume was an independent predictor of unfavorable OS (HR=3.597, 95% CI: 1.160-11.153, p=0.027) in high-grade glioma. Our findings suggest that the hippocampus has a remarkable degree of plasticity in response to pathological stimulation of glioma and that the hippocampal reaction to glioma may be related to tumor malignancy.

Structural and Functional Alterations in the Contralesional Medial Temporal Lobe in Glioma Patients.

BACKGROUND: The human brain has an extraordinary ability to functionally change or reorganize its structure in response to disease. The aim of this study is to assess the structural and functional plasticity of contralesional medial temporal lobe (MTL) in patients with unilateral MTL glioma. METHODS: Sixty-eight patients with unilateral MTL glioma (left MTL glioma, n = 33; right MTL glioma, n = 35) and 40 healthy controls were recruited and scanned with 3D T1 MRI and rest-fMRI. We explored the structure of the contralesional MTL using voxel-based morphometry (VBM) and assessed the memory networks of the contralesional hemisphere using resting-state functional connectivity (rs-FC). The association between FC and cognitive function was assessed with partial correlation analysis. RESULTS: Compared with healthy controls, both patient groups exhibited (1) a large cluster of voxels with gray matter (GM) volume decrease in the contralesional MTL using region of interest (ROI)-based VBM analysis (cluster level p < 0.05, FDR corrected); and (2) decreased intrahemispheric FC between the posterior hippocampus (pHPC) and posterior cingulate cortex (PCC) (p < 0.01, Bonferroni corrected). Intrahemispheric FC between the pHPC and PCC was positively correlated with cognitive function in both patient groups. CONCLUSION: Using multi-modality brain imaging tools, we found structural and functional changes in the contralesional MTL in patients with unilateral MTL glioma. These findings suggest that the contralesional cortex may have decompensation of structure and function in patients with unilateral glioma, except for compensatory structural and functional adaptations. Our study provides additional insight into the neuroanatomical and functional network changes in the contralesional cortex in patients with glioma.

The role of serum growth hormone and insulin-like growth factor-1 in adult humans brain morphology.

Growth hormone (GH) and its anabolic mediator, insulin-like growth factor-1 (IGF-1), have a critical role in the central nervous system. However, their detailed roles in the adult human brain are not clear. In this study, structural MRIs of 48 patients with GH-secreting pituitary adenoma (GH-PA), 48 sex- and age-matched clinical Non-Functional pituitary adenoma patients (NonFun-PA) and healthy controls (HCs) were assessed using voxel-based morphometry (VBM) and region-based morphometry (RBM). Correlation analyses helped determine the relationships between serum hormone levels and brain structure. The whole-brain gray matter volume (GMV) and white matter volume (WMV) significantly increased at the expense of cerebrospinal fluid volume (CSFV) in GH-PA (Bonferroni corrected, p<0.01). The increase in GMV and reduction in CSFV were significantly correlated with serum GH/IGF-1 levels (p<0.05). VBM showed significant correlations of the GMV/WMV alteration pattern between GH-PA vs HCs and GH-PA vs NonFun-PA and widespread bilateral clusters of significantly increased GMV and WMV in GH-PA (pFDR<0.05). RBM showed obviously increased GMV/WMV in 54 of 68 brain regions (p<0.05) in GH-PA compared to HCs. Our results provide imaging evidence that serum GH/IGF-1 contributes to brain growth, which may be a potential treatment option for neurodegenerative disorders and brain injury in humans.

Brain Morphometric and Functional Magnetic Resonance Imaging Study on Patients with Visual Field Defects Resulting from Suprasellar Tumors: Preoperative and Postoperative Assessment.

OBJECTIVE: The aim of this study was to investigate the structural and functional changes in the visual cortex in patients with suprasellar tumor with recovery of visual field defects at different times before and after surgical decompression of the optic nerves. METHODS: Twenty-one patients with suprasellar tumor with visual field defects were scanned with structural images and resting-state functional magnetic resonance imaging at 1 week preoperation, 1 week postoperation, and 1 month postoperation. Paired-sample t test was performed on the gray matter volume (GMV) within the occipital cortex, and the significance level was set at false discovery rate (FDR)-adjusted P < 0.05 voxel level to define the region of interest (ROI). One-way analysis of variance was performed on GMV and amplitude of low frequency fluctuation (ALFF) within the ROI. Pearson coefficients were calculated between changes of GMV and ALFF within the ROI and clinical factors. RESULTS: The GMV in the bilateral pericalcarine cortex increased significantly at 1 month postoperation compared with the preoperative period (FDR-adjusted P < 0.05), with correlation to visual field defects. ALFF values in the bilateral pericalcarine cortex at 1 month postoperation were significantly higher than preoperative values. CONCLUSIONS: The postoperative visual improvement can be reflected in the increased GMV and ALFF of the bilateral pericalcarine cortex at 1 month postoperation, which suggests that an experience-dependent plasticity of the visual cortex was induced by an increase in sensory input.

Increased resting-state functional connectivity in suprasellar tumor patients with postoperative visual improvement.

Background and Objective: Large suprasellar tumors often compress the optic chiasm and give rise to visual impairment. Most patients have significantly improved visual function at 1 to 4 months after chiasmal decompression surgery, and only a few individuals regain normal vision at 1 week after surgery. How the recovery of visual function in these patients affects the visual cortex is not fully understood. In this study, we aimed to investigate alterations in brain functional connectivity (FC) in suprasellar tumor patients with visual improvement using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: This longitudinal study was conducted on 13 suprasellar tumor patients who had ophthalmological examinations and rs-fMRI at the following time points: within 1-week preoperation (Pre-op), 1-week postoperation (Post-1w) and 1-month postoperation (Post-1m). The visual impairment score (VIS), local functional correlation (LCOR) and FC values were subjected to one-way ANOVA. Pearson correlation coefficients between changes in the LCOR and clinical factors were calculated. Results: The VIS was significantly decreased at both Post-1w and Post-1m compared to that at Pre-op. Whole-brain analysis of LCOR values showed that the left V1 (primary occipital cortex) was increased significantly at Post-1m compared to that at Pre-op (p < 0.05, FDR corrected). ROI analysis exhibited a significant negative correlation between the LCOR and VIS changes at Post-1m compared to those at Pre-op (p < 0.05, r = - 0.60). FC analysis within the visual network showed that the FC strengths were significantly increased between the left V5 and the left V4, right V3a, left V3, left V2d, and right V5 at Post-1m compared to those at Pre-op (p < 0.05, FDR corrected). Additionally, the FC strengths were significantly increased between the left V5 and the left V1, right orbital-frontal gyrus and left posterior supramarginal gyrus at the whole-brain network level at Post-1m compared to those at Pre-op (p < 0.05, FDR corrected). Conclusions: Postoperative visual improvement can be reflected by the increased FC of the visual cortex at Post-1w and Post-1m, especially at Post-1m. The LCOR value of the left V1 was associated with improved visual outcomes and may be used to objectively assess early visual recovery after chiasmal decompression at Post-1m.

High-Dose Neural Stem/Progenitor Cell Transplantation Increases Engraftment and Neuronal Distribution and Promotes Functional Recovery in Rats after Acutely Severe Spinal Cord Injury.

Severe spinal cord injury (SCI) leads to permanent, complete paraplegia and places considerable mental and economic burdens on patients, compared with mild to moderate SCI. However, the dose-related effects of the neural stem/precursor cell (NSPC) transplantation on the injury microenvironment, NSPC survival, axonal growth, neuronal distribution, the composition of neurons, oligodendrocytes, and astrocytes in the lesion area and functional recovery have not yet been quantitatively evaluated in the context of severe SCI. In our study, we acutely transplanted 2.5 × 104 or 1.5 × 105 NSPCs/µl into the site of transection SCI. We found that high-dose NSPC transplantation exerted immunomodulatory and neuroprotective effects in the acute phase of severe SCI. In addition, one week later, a remarkable positive relationship was observed between the transplantation dose and the number of surviving NSPCs in severe SCI. At 8 weeks postgrafting, subjects that received the higher cell dose exhibited abundant nerve regeneration, extensive neuronal distribution, increased proportions of neurons and oligodendrocytes, and nascent functional neural network formation in the lesion area. Notably, a significant functional recovery was also observed. Our data suggest that it is important to consider potential dose-related effects on donor cell survival, neuronal distribution, and locomotor recovery in the development of preclinical NSPC transplantation therapy for severe SCI.

Role of EGFL7/EGFR-signaling pathway in migration and invasion of growth hormone-producing pituitary adenomas.

Currently, the primary therapeutic strategy for most growth hormone-producing pituitary adenomas (GHPA) is surgery. Due to the invasiveness of GHPA, high recurrence has limited the benefit of complete adenoma removal surgery. Epidermal growth factor-like domain 7 (EGFL7) is a secreted factor implicated in tumor angiogenesis, growth, invasiveness and metastasis in GHPA. Herein, we observed that the expression level of EGFL7 and p-EGFR in invasive GHPA was much higher than that of non-invasive GHPA. The overexpression of EGFL7 was positively correlated with activation of EGFR (p-EGFR). Noticeably, EGFL7 knockdown significantly inhibited activation of EGFR signaling cascades, including p-ERGR, p-AKT and p-ERK. Further studies showed that EGFL7 knockdown or pharmacological inhibition of EGFR-pathway, using EGFR inhibitor Tyrphostin AG-1478, significantly suppressed migration and invasion of GH3 and GT1-1 cells. In summary, our findings suggest that EGFL7 is a key factor for regulation of EGFR signaling pathway and plays an important role in migration and invasion of invasive GHPA.