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Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy.

ABSTRACT: Ischemic stroke is a damaging cerebral vascular disease associated with high disability and mortality rates worldwide. In spite of the continuous development of new diagnostic and prognostic methods, early detection and outcome prediction are often very difficult. The neurovascular unit (NVU) is a complex multicellular entity linking the interactions between neurons, glial cells, and brain vessels. Novel research has revealed that exosome-mediated transfer of microRNAs plays an important role in cell-to-cell communication and, thus, is integral in the multicellular crosstalk within the NVU. After a stroke, NVU homeostasis is altered, which induces the release of several potential biomarkers into the blood vessels. The addition of biological data representing all constituents of the NVU to clinical and neuroradiological findings can significantly advance stroke evaluation and prognosis. In this review, we present the current literature regarding the possible beneficial roles of exosomes derived from the components of the NVU and multipotent mesenchymal stem cells in preclinical studies of ischemic stroke. We also discuss the most relevant clinical trials on the diagnostic and prognostic roles of exosomes in stroke patients.

SUBMITTER: Forro T

PROVIDER: S-EPMC8198979 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy.

Forró Timea T Bajkó Zoltán Z Bălașa Adrian A Bălașa Rodica R

International journal of molecular sciences 20210525 11

Ischemic stroke is a damaging cerebral vascular disease associated with high disability and mortality rates worldwide. In spite of the continuous development of new diagnostic and prognostic methods, early detection and outcome prediction are often very difficult. The neurovascular unit (NVU) is a complex multicellular entity linking the interactions between neurons, glial cells, and brain vessels. Novel research has revealed that exosome-mediated transfer of microRNAs plays an important role in ...[more]

PMID: 34070696

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Project description:BackgroundIn ischemic stroke, the function of the cerebral vasculature is impaired. This vascular structure is formed by the so-called neurovascular unit (NVU). A better understanding of the mechanisms involved in NVU dysfunction and recovery may lead to new insights for the development of highly sought therapeutic approaches. To date, there remains an unmet need for complex human in vitro models of the NVU to study ischemic events seen in the human brain.MethodsWe here describe the development of a human NVU on-a-chip model using a platform that allows culture of 40 chips in parallel. The model comprises a perfused vessel of primary human brain endothelial cells in co-culture with induced pluripotent stem cell derived astrocytes and neurons. Ischemic stroke was mimicked using a threefold approach that combines chemical hypoxia, hypoglycemia, and halted perfusion.ResultsImmunofluorescent staining confirmed expression of endothelial adherens and tight junction proteins, as well as astrocytic and neuronal markers. In addition, the model expresses relevant brain endothelial transporters and shows spontaneous neuronal firing. The NVU on-a-chip model demonstrates tight barrier function, evidenced by retention of small molecule sodium fluorescein in its lumen. Exposure to the toxic compound staurosporine disrupted the endothelial barrier, causing reduced transepithelial electrical resistance and increased permeability to sodium fluorescein. Under stroke mimicking conditions, brain endothelial cells showed strongly reduced barrier function (35-fold higher apparent permeability) and 7.3-fold decreased mitochondrial potential. Furthermore, levels of adenosine triphosphate were significantly reduced on both the blood- and the brain side of the model (4.8-fold and 11.7-fold reduction, respectively).ConclusionsThe NVU on-a-chip model presented here can be used for fundamental studies of NVU function in stroke and other neurological diseases and for investigation of potential restorative therapies to fight neurological disorders. Due to the platform's relatively high throughput and compatibility with automation, the model holds potential for drug compound screening.

Project description:Background and purposeThis study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke.MethodsThis cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort.ResultsThis study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692-0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077-0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels.ConclusionStroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

Project description:PurposeWe aimed to analyze retinal neurovascular unit (RNVU) alterations and function via optical coherence tomography angiography (OCTA) and full-field electroretinography (ERG) in patients with ischemic stroke (IS).MethodsOCTA was used to measure RNVU changes in 229 participants (101 with IS and 128 healthy controls). The RETeval device was used to record full-field electroretinograms (FERGs) in 40 participants (14 with IS and 26 healthy controls). Logistic regression models for IS were constructed. Receiver operating characteristic (ROS) curves were constructed to assess the predictive value of various models for IS.ResultsPatients with ipsilateral internal carotid artery stenosis (ICAS) had a greater occurrence of IS. A decrease in the vascular density (VD) of the parafovea, FD-300, and nasal optic disc; a decrease in the thickness of the retinal nerve fiber layer (RNFL) around the nasal optic disc; and an increase in the acircularity index (AI) were observed in patients with IS (P < 0.05). An increase in the AI was identified as a risk factor for IS, whereas the other factors were found to be protective factors. The IS group presented a delayed a-wave implicit time and decreased b-wave amplitudes at the scotopic point. By incorporating traditional risk factors, the degree of ipsilateral ICAS, and OCTA parameters, a high predictive value for IS was achieved (area under the curve [AUC] = 0.933).ConclusionsPatients with IS without visible fundus lesions presented changes in the RNVU, characterized by reductions in retinal VD and RNFL thickness, alongside dysfunction of photoreceptor cells and bipolar cells. The combination of RNVU changes with traditional risk factors can enhance the prediction of IS, which provides valuable guidance for monitoring this disease.Translational relevanceThis study demonstrated that the combination of OCTA parameters, the degree of ipsilateral ICAS, and traditional risk factors could can enhance the prediction of IS. These findings provide valuable guidance for monitoring IS by assessing RNVUs.

Dataset Information

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy.

Publications

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy.

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