Fluids and Barriers of the CNS最新文献

{"title":"Choroid plexus aging: structural and vascular insights from the HCP-aging dataset.","authors":"Zhe Sun, Chenyang Li, Jiangyang Zhang, Thomas Wisniewski, Yulin Ge","doi":"10.1186/s12987-024-00603-y","DOIUrl":"10.1186/s12987-024-00603-y","url":null,"abstract":"<p><strong>Background: </strong>The choroid plexus (ChP), a highly vascularized structure within the ventricles, is essential for cerebrospinal fluid (CSF) production and metabolic waste clearance, crucial for neurofluid homeostasis and cognitive function. ChP enlargement is seen in normal aging and neurodegenerative diseases like Alzheimer's disease (AD). Despite its key role of in the blood-CSF barrier (BCSFB), detailed studies on age-related changes in its perfusion and microstructure remain limited.</p><p><strong>Methods: </strong>We analyzed data from 641 healthy individuals aged between 36 and 90, using the Human Connectome Project Aging (HCP-A) dataset. Volumetric, perfusion, and diffusion metrics of the ChP were derived from structural MRI, arterial spin labeling (ASL), and diffusion-weighted imaging (DWI), respectively. Partial correlations were used to explore age-related ChP changes, and independent t-tests to examine sex differences across age decades. One-way ANOVA was employed to compare perfusion characteristics among ChP, gray matter (GM), and white matter (WM). Relationships between volume, perfusion, and diffusion were investigated, adjusting for age and sex. Additionally, the distribution of cyst-like structures within the ChP and their diffusion/perfusion MRI characteristics were analyzed across different age groups.</p><p><strong>Results: </strong>The ChP undergoes notable changes with age, including an increase in volume (r² = 0.2, P < 0.001), a decrease in blood flow (r² = 0.17, P < 0.001), and elevated mean diffusivity (MD) values (r² = 0.16, P < 0.001). Perfusion characteristics showed significant differences between the ChP, GM, and WM (P < 0.001). Both the ChP and GM exhibited age-related declines in CBF, with a more pronounced decline in the ChP. A negative correlation was observed between the age-related increase in ChP volume and the decrease in CBF, suggesting compensatory dystrophic hyperplasia in response to perfusion decline. Cyst-like structures in ChP, characterized by lower MD and reduced CBF, were found to be more prevalent in older individuals.</p><p><strong>Conclusions: </strong>Our findings provide a detailed quantitative assessment of age-related changes in ChP perfusion and diffusion, which may affect CSF production and circulation, potentially leading to waste solute accumulation and cognitive impairment.</p><p><strong>Grant support: </strong>This work was supported in part by the NIH U01AG052564, P30AG066512, P01AG060882, RF1 NS110041, R01 NS108491, U24 NS135568.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"98"},"PeriodicalIF":5.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive MRI of blood-cerebrospinal fluid-barrier function in a mouse model of Alzheimer's disease: a potential biomarker of early pathology.","authors":"Charith Perera, Renata Cruz, Noam Shemesh, Tânia Carvalho, David L Thomas, Jack Wells, Andrada Ianuș","doi":"10.1186/s12987-024-00597-7","DOIUrl":"10.1186/s12987-024-00597-7","url":null,"abstract":"<p><strong>Background: </strong>Choroid plexus (CP) or blood-cerebrospinal fluid-barrier (BCSFB) is a unique functional tissue which lines the brain's fluid-filled ventricles, with a crucial role in CSF production and clearance. BCSFB dysfunction is thought to contribute to toxic protein build-up in neurodegenerative disorders, including Alzheimer's disease (AD). However, the dynamics of this process remain unknown, mainly due to the paucity of in-vivo methods for assessing CP function.</p><p><strong>Methods: </strong>We harness recent developments in Arterial Spin Labelling MRI to measure water delivery across the BCSFB as a proxy for CP function, as well as cerebral blood flow (CBF), at different stages of AD in the widely used triple transgenic mouse model (3xTg), with ages between 8 and 32 weeks. We further compared the MRI results with Y-maze behaviour testing, and histologically validated the expected pathological changes, which recapitulate both amyloid and tau deposition.</p><p><strong>Results: </strong>Total BCSFB-mediated water delivery is significantly higher in 3xTg mice (> 50%) from 8 weeks (preclinical stage), an increase which is not explained by differences in ventricular volumes, while tissue parameters such as CBF and T1 are not different between groups at all ages. Behaviour differences between the groups were observed starting at 20 weeks, especially in terms of locomotion, with 3xTg animals showing a significantly smaller number of arm entries in the Y-maze.</p><p><strong>Conclusions: </strong>Our work strongly suggests the involvement of CP in the early stages of AD, before the onset of symptoms and behavioural changes, providing a potential biomarker of pathology.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"97"},"PeriodicalIF":5.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Effects of aging on hydrocephalus after intraventricular hemorrhage.","authors":"Yingfeng Wan, Feng Gao, Fenghui Ye, Weiming Yang, Ya Hua, Richard F Keep, Guohua Xi","doi":"10.1186/s12987-024-00591-z","DOIUrl":"10.1186/s12987-024-00591-z","url":null,"abstract":"","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"96"},"PeriodicalIF":5.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced oxycodone brain delivery in rats due to lipopolysaccharide-induced inflammation: microdialysis insights into brain disposition and sex-specific pharmacokinetics.","authors":"Frida Bällgren, Margareta Hammarlund-Udenaes, Irena Loryan","doi":"10.1186/s12987-024-00598-6","DOIUrl":"10.1186/s12987-024-00598-6","url":null,"abstract":"<p><strong>Background: </strong>Oxycodone, a widely used opioid analgesic, has an unbound brain-to-plasma concentration ratio (K_p,uu) greater than unity, indicating active uptake across brain barriers associated with the putative proton-coupled organic cation (H⁺/OC) antiporter system. With this study, we aimed to elucidate oxycodone's CNS disposition during lipopolysaccharide (LPS)-induced systemic inflammation in Sprague-Dawley rats.</p><p><strong>Methods: </strong>Using brain microdialysis, we dynamically and simultaneously monitored unbound oxycodone concentrations in blood, striatum, lateral ventricle, and cisterna magna following intravenous administration of oxycodone post-LPS challenge.</p><p><strong>Results: </strong>Our results indicated a reduced, sex-independent brain net uptake of oxycodone across the blood-brain barrier (BBB) measured in the striatum. Notably, the LPS challenge has significantly altered the systemic pharmacokinetics (PK) of oxycodone, in a sex-specific manner, leading to lower clearance and higher blood concentrations in females compared to LPS-treated males and healthy rats of both sexes. Proteomic analysis using Olink Target 96 Mouse Exploratory assay confirmed the induction of systemic inflammation and neuroinflammation. The inflammation led to an increased paracellular transport, measured using 4 kDa dextran, while preserving net active uptake of oxycodone across both BBB and the blood-cerebrospinal fluid barrier (BCSFB), with K_p,uu values of 2.7 and 2.5, respectively. The extent of uptake was 1.6-fold lower (p < 0.0001) at the BBB and unchanged at the BCSFB after the LPS challenge compared to that in healthy rats. However, the mean exposure of unbound oxycodone in the brain following LPS was similar to that in healthy rats, primarily due to the LPS-induced changes in systemic exposure.</p><p><strong>Conclusions: </strong>These findings highlight the dissimilar responses at blood-brain interfaces during LPS-induced inflammation. Advancing the knowledge of neuropharmacokinetic mechanisms, specifically those involving the H⁺/OC antiporter system, will enable the development of more effective therapeutic strategies during inflammation conditions.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"95"},"PeriodicalIF":5.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relaxation-exchange magnetic resonance imaging (REXI): a non-invasive imaging method for evaluating trans-barrier water exchange in the choroid plexus.","authors":"Xuetao Wu, Qingping He, Yu Yin, Shuyuan Tan, Baogui Zhang, Weiyun Li, Yi-Cheng Hsu, Rong Xue, Ruiliang Bai","doi":"10.1186/s12987-024-00589-7","DOIUrl":"10.1186/s12987-024-00589-7","url":null,"abstract":"<p><strong>Background: </strong>The choroid plexus (CP) plays a crucial role in cerebrospinal fluid (CSF) production and brain homeostasis. However, non-invasive imaging techniques to assess its function remain limited. This study was conducted to develop a novel, contrast-agent-free MRI technique, termed relaxation-exchange magnetic resonance imaging (REXI), for evaluating CP-CSF water transport, a potential biomarker of CP function.</p><p><strong>Methods: </strong>REXI utilizes the inherent and large difference in magnetic resonance transverse relaxation times (T₂s) between CP tissue (e.g., blood vessels and epithelial cells) and CSF. It uses a filter block to remove most CP tissue magnetization (shorter T₂), a mixing block for CP-CSF water exchange with mixing time t_m, and a detection block with multi-echo acquisition to determine the CP/CSF component fraction after exchange. The REXI pulse sequence was implemented on a 9.4 T preclinical MRI scanner. For validation of REXI's ability to measure exchange, we conducted preliminary tests on urea-water proton-exchange phantoms with various pH levels. We measured the steady-state water efflux rate from CP to CSF in rats and tested the sensitivity of REXI in detecting CP dysfunction induced by the carbonic anhydrase inhibitor acetazolamide.</p><p><strong>Results: </strong>REXI pulse sequence successfully captured changes in the proton exchange rate (from short-T₂ component to long-T₂ component [i.e., k_sl]) of urea-water phantoms at varying pH, demonstrating its sensitivity to exchange processes. In rat CP, REXI significantly suppressed the CP tissue signal, reducing the short-T₂ fraction (f_short) from 0.44 to 0.23 (p < 0.0001), with significant recovery to 0.28 after a mixing time of 400 ms (p = 0.014). The changes in f_short at various mixing times can be accurately described by a two-site exchange model, yielding a steady-state water efflux rate from CP to CSF (i.e., k_bc) of 0.49 s^-1. A scan-rescan experiment demonstrated that REXI had excellent reproducibility in measuring k_bc (intraclass correlation coefficient = 0.90). Notably, acetazolamide-induced CSF reduction resulted in a 66% decrease in k_bc within rat CP.</p><p><strong>Conclusions: </strong>This proof-of-concept study demonstrates the feasibility of REXI for measuring trans-barrier water exchange in the CP, offering a promising biomarker for future assessments of CP function.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"94"},"PeriodicalIF":5.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the transcription factor NRF2 in maintaining the integrity of the Blood-Brain Barrier.","authors":"Eduardo Cazalla, Antonio Cuadrado, Ángel Juan García-Yagüe","doi":"10.1186/s12987-024-00599-5","DOIUrl":"10.1186/s12987-024-00599-5","url":null,"abstract":"<p><strong>Background: </strong>The Blood-Brain Barrier (BBB) is a complex and dynamic interface that regulates the exchange of molecules and cells between the blood and the central nervous system. It undergoes structural and functional throughout oxidative stress and inflammation, which may compromise its integrity and contribute to the pathogenesis of neurodegenerative diseases.</p><p><strong>Main body: </strong>Maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. NRF2 is the main transcription factor that regulates cellular redox balance and inflammation-related gene expression. It has also demonstrated a potential role in regulating tight junction integrity and contributing to the inhibition of ECM remodeling, by reducing the expression of several metalloprotease family members involved in maintaining BBB function. Overall, we review current insights on the role of NRF2 in addressing protection against the effects of BBB dysfunction, discuss its involvement in BBB maintenance in different neuropathological diseases, as well as, some of its potential activators that have been used in vitro and in vivo animal models for preventing barrier dysfunction.</p><p><strong>Conclusions: </strong>Thus, emerging evidence suggests that upregulation of NRF2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase its protection.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"93"},"PeriodicalIF":5.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutated LRRK2 induces a reactive phenotype and alters migration in human iPSC-derived pericyte-like cells.","authors":"Sanni Peltonen, Tuuli-Maria Sonninen, Jonna Niskanen, Jari Koistinaho, Marika Ruponen, Šárka Lehtonen","doi":"10.1186/s12987-024-00592-y","DOIUrl":"10.1186/s12987-024-00592-y","url":null,"abstract":"<p><strong>Background: </strong>Pericytes play a crucial role in controlling inflammation and vascular functions in the central nervous system, which are disrupted in Parkinson's disease (PD). Still, there is a lack of studies on the impact of pericytes on neurodegenerative diseases, and their involvement in the pathology of PD is unclear. Our objective was to investigate the molecular and functional differences between healthy pericytes and pericytes with the LRRK2 G2019S mutation, which is one of the most common mutations associated with PD.</p><p><strong>Methods: </strong>Our study employed pericyte-like cells obtained from induced pluripotent stem cells produced from PD patients with the LRRK2 G2019S mutation as well as from healthy individuals. We examined the gene expression profiles of the cells and analyzed how the alterations reflect on their functionality.</p><p><strong>Results: </strong>We have shown differences in the expression of genes related to inflammation and angiogenesis. Furthermore, we observe modified migration speed in PD pericyte-like cells as well as enhanced secretion of inflammatory mediators, such as soluble VCAM-1 and MCP-1, in these pericyte-like cells following exposure to proinflammatory stimuli.</p><p><strong>Conclusions: </strong>In summary, our findings support the notion that pericytes play a role in the inflammatory and vascular changes observed in PD. Further investigation of pericytes could provide valuable insight into understanding the pathogenesis of PD.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"92"},"PeriodicalIF":5.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C1-inhibitor to prevent intracerebral hemorrhage-related secondary brain injury.","authors":"Kevin Akeret, Bart R Thomson, Subhajit Ghosh, Marc Nolte, Urs Fischer, Rok Humar, Luca Regli, Dominik J Schaer, Michael Hugelshofer, Raphael M Buzzi","doi":"10.1186/s12987-024-00594-w","DOIUrl":"10.1186/s12987-024-00594-w","url":null,"abstract":"<p><strong>Background: </strong>Preclinical studies indicate that the systemic application of C1-inhibitor, clinically used to treat hereditary angioedema, reduces secondary brain injury after ischemic stroke. This study assessed the effect of C1-inhibitor on secondary brain injury after hemorrhagic stroke.</p><p><strong>Methods: </strong>We used an established striatal whole-blood injection mouse model to mimic intracerebral hemorrhage-related secondary brain injury. Based on the spatiotemporal dynamics in our model, we calculated the necessary sample size (n = 24) and determined the most sensitive time point to detect potential group differences (48 h) prior to the experiments. The experimental setup, tissue processing and image analysis adhered to our published protocol. We randomized mice into three groups: C1-inhibitor treatment, placebo, and sham. Histology was standardized by taking eight anatomically predefined slices across the entire lesion. Lesion size, vascular leakage, and inflammatory responses were assessed using automated thresholding and dextran/ICAM1/CD45 intensity mapping. Investigators were blinded to group allocation during the experiment, tissue processing, and image analysis.</p><p><strong>Results: </strong>Whole blood injection resulted in significantly larger lesion size and more pronounced vascular leakage and cellular inflammation compared to the sham group. However, there was no difference in lesion size or inflammatory markers between the C1-inhibitor and placebo groups. In addition, there was no difference in the inflammatory response of the choroid plexus, which has been identified as a central organ orchestrating inflammation after intracerebral hemorrhage.</p><p><strong>Conclusion: </strong>The protective effect of C1-inhibitor might be isolated to pathophysiological processes with a predominant thromboinflammatory component, as in ischemia-reperfusion, but less so in permanent ischemia or intracerebral hemorrhage.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"91"},"PeriodicalIF":5.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring dysfunctional barrier phenotypes associated with glaucoma using a human pluripotent stem cell-based model of the neurovascular unit.","authors":"Sailee S Lavekar, Jason M Hughes, Cátia Gomes, Kang-Chieh Huang, Jade Harkin, Scott G Canfield, Jason S Meyer","doi":"10.1186/s12987-024-00593-x","DOIUrl":"10.1186/s12987-024-00593-x","url":null,"abstract":"<p><p>Glaucoma is a neurodegenerative disease that results in the degeneration of retinal ganglion cells (RGCs) and subsequent loss of vision. While RGCs are the primary cell type affected in glaucoma, neighboring cell types selectively modulate RGCs to maintain overall homeostasis. Among these neighboring cell types, astrocytes, microvascular endothelial cells (MVECs), and pericytes coordinate with neurons to form the neurovascular unit that provides a physical barrier to limit the passage of toxic materials from the blood into neural tissue. Previous studies have demonstrated that these barrier properties may be compromised in the progression of glaucoma, yet mechanisms by which this happens have remained incompletely understood. Thus, the goals of this study were to adapt a human pluripotent stem cell (hPSC)-based model of the neurovascular unit to the study of barrier integrity relevant to glaucoma. To achieve this, hPSCs were differentiated into the cell types that contribute to this barrier, including RGCs, astrocytes, and MVECs, then assembled into an established Transwell^®-insert model. The ability of these cell types to contribute to an in vitro barrier model was tested for their ability to recapitulate characteristic barrier properties. Results revealed that barrier properties of MVECs were enhanced when cultured in the presence of RGCs and astrocytes compared to MVECs cultured alone. Conversely, the versatility of this system to model aspects of barrier dysfunction relevant to glaucoma was tested using an hPSC line with a glaucoma-specific Optineurin (E50K) mutation as well as a paired isogenic control, where MVECs then exhibited reduced barrier integrity. To identify factors that could result in barrier dysfunction, results revealed an increased expression of TGFβ2 in glaucoma-associated OPTN(E50K) astrocytes, indicating a potential role for TGFβ2 in disease manifestation. To test this hypothesis, we explored the ability to modulate exogenous TGFβ2 in both isogenic control and OPTN(E50K) experimental conditions. Collectively, the results of this study indicated that the repurposing of this in vitro barrier model for glaucoma reliably mimicked some aspects of barrier dysfunction, and may serve as a platform for drug discovery, as well as a powerful in vitro model to test the consequences of barrier dysfunction upon RGCs in glaucoma.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"90"},"PeriodicalIF":5.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-brain barrier permeability increases with the differentiation of glioblastoma cells in vitro.","authors":"Sabrina Digiovanni, Martina Lorenzati, Olga Teresa Bianciotto, Martina Godel, Simona Fontana, Muhlis Akman, Costanzo Costamagna, Pierre-Olivier Couraud, Annalisa Buffo, Joanna Kopecka, Chiara Riganti, Iris Chiara Salaroglio","doi":"10.1186/s12987-024-00590-0","DOIUrl":"10.1186/s12987-024-00590-0","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) is an aggressive tumor, difficult to treat pharmacologically because of the blood-brain barrier (BBB), which is rich in ATP-binding cassette (ABC) transporters and tight junction (TJ) proteins. The BBB is disrupted within GBM bulk, but it is competent in brain-adjacent-to-tumor areas, where eventual GBM foci can trigger tumor relapse. How GBM cells influence the permeability of BBB is poorly investigated.</p><p><strong>Methods: </strong>To clarify this point, we co-cultured human BBB models with 3 patient-derived GBM cells, after separating from each tumor the stem cell/neurosphere (SC/NS) and the differentiated/adherent cell (AC) components. Also, we set up cultures of BBB cells with the conditioned medium of NS or AC, enriched or depleted of IL-6. Extracellular cytokines were measured by protein arrays and ELISA. The intracellular signaling in BBB cells was measured by immunoblotting, in the presence of STAT3 pharmacological inhibitor or specific PROTAC. The competence of BBB was evaluated by permeability assays and TEER measurement.</p><p><strong>Results: </strong>The presence of GBM cells or their conditioned medium increased the permeability to doxorubicin, mitoxantrone and dextran-70, decreased TEER, down-regulated ABC transporters and TJ proteins at the transcriptional level. These effects were higher with AC or their medium than with NS. The secretome analysis identified IL-6 as significantly more produced by AC than by NS. Notably, AC-conditioned medium treated with an IL-6 neutralizing antibody reduced the BBB permeability to NS levels, while NS-conditioned medium enriched with IL-6 increased BBB permeability to AC levels. Mechanistically, IL-6 released by AC GBM cells activated STAT3 in BBB cells. In turn, STAT3 down-regulated ABC transporter and TJ expression, increased permeability and decreased TEER. The same effects were obtained in BBB cells treated with STA-21, a pharmacological inhibitor of STAT3, or with a PROTAC targeting STAT3.</p><p><strong>Conclusions: </strong>Our work demonstrates for the first time that the degree of GBM differentiation influences BBB permeability. The crosstalk between GBM cells that release IL-6 and BBB cells that respond by activating STAT3, controls the expression of ABC transporters and TJ proteins on BBB. These results may pave the way for novel therapeutic tools to tune BBB permeability and improve drug delivery to GBM.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"89"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}