The neurovascular unit-on-a-chip: modeling ischemic stroke to stem cell therapy.
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ABSTRACT:
SUBMITTER: Kim S
PROVIDER: S-EPMC10883497 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
Publications
The neurovascular unit-on-a-chip: modeling ischemic stroke to stem cell therapy.
Kim Seonghun S Kim Minjun M Grant Gerald A GA Lee Wonjae W
Neural regeneration research 20230922 7
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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.
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Project description:Organ-on-a-chip in vitro platforms accurately mimic complex microenvironments offering the ability to recapitulate and dissect mechanisms of physiological and pathological settings, revealing their major importance to develop new therapeutic targets. Bone diseases, such as osteoarthritis, are extremely complex, comprising of the action of inflammatory mediators leading to unbalanced bone homeostasis and de-regulation of sensory innervation and angiogenesis. Although there are models to mimic bone vascularization or innervation, in vitro platforms merging the complexity of bone, vasculature, innervation, and inflammation are missing. Therefore, in this study a microfluidic-based neuro-vascularized bone chip (NVB chip) is proposed to 1) model the mechanistic interactions between innervation and angiogenesis in the inflammatory bone niche, and 2) explore, as a screening tool, novel strategies targeting inflammatory diseases, using a nano-based drug delivery system. It is possible to set the design of the platform and achieve the optimized conditions to address the neurovascular network under inflammation. Moreover, this system is validated by delivering anti-inflammatory drug-loaded nanoparticles to counteract the neuronal growth associated with pain perception. This reliable in vitro tool will allow understanding the bone neurovascular system, enlightening novel mechanisms behind the inflammatory bone diseases, bone destruction, and pain opening new avenues for new therapies discovery.
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Project description:The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.
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Project description: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.
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Project description:The regenerative potential of brain has led to emerging therapies that can cure clinico-motor deficits after neurological diseases. Bone marrow mononuclear cell therapy is a great hope to mankind as these cells are feasible, multipotent and aid in neurofunctional gains in Stroke patients.This study evaluates safety, feasibility and efficacy of autologous mononuclear (MNC) stem cell transplantation in patients with chronic ischemic stroke (CIS) using clinical scores and functional imaging (fMRI and DTI).Non randomised controlled observational study Study: Twenty four (n=24) CIS patients were recruited with the inclusion criteria as: 3 months-2years of stroke onset, hand muscle power (MRC grade) at least 2; Brunnstrom stage of recovery: II-IV; NIHSS of 4-15, comprehendible. Fugl Meyer, modified Barthel Index (mBI) and functional imaging parameters were used for assessment at baseline, 8 weeks and at 24 weeks. Twelve patients were administered with mean 54.6 million cells intravenously followed by 8 weeks of physiotherapy. Twelve patients served as controls. All patients were followed up at 24 weeks.The laboratory and radiological outcome measures were within normal limits in MNC group. Only mBI showed statistically significant improvement at 24 weeks (p<0.05) whereas the mean FM, MRC, Ashworth tone scores in the MNC group were high as compared to control group. There was an increased number of cluster activation of Brodmann areas BA 4, BA 6 post stem cell infusion compared to controls indicating neural plasticity. Cell therapy is safe and feasible which may facilitate restoration of function in CIS.
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Project description:The neurovascular unit (NVU) is an anatomical group of cells that establishes the blood-brain barrier (BBB) and coordinates cerebral blood flow in association with neuronal function. In cerebral gray matter, cellular constituents of the NVU include endothelial cells and associated pericytes, astrocytes, neurons, and microglia. Dysfunction of the NVU is a common feature of diseases that affect the CNS, such as ischemic stroke. High-level evaluation of these NVU changes requires the use of imaging modalities that can enable the visualization of various cell types under disease conditions. In this study, we applied our confocal microscopy strategy using commercially available labeling reagents to, for the first time, simultaneously investigate associations between endothelial cells, the vascular basal lamina, pericytes, microglia, astrocytes and/or astrocyte end-feet, and neurites in both healthy and ischemic brain tissue. This allowed us to demonstrate ischemia-induced astrocyte activation, neurite loss, and microglial migration toward blood vessels in a single confocal image. Furthermore, our labeling cocktail enabled a precise quantification of changes in neurites and astrocyte reactivity, thereby showing the relationship between different NVU cellular constituents in healthy and diseased brain tissue. The application of our imaging approach for the simultaneous visualization of multiple NVU cell types provides an enhanced understanding of NVU function and pathology, a state-of-the-art advancement that will facilitate the development of more effective treatment strategies for diseases of the CNS that exhibit neurovascular dysfunction, such as ischemic stroke.
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Project description:Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.
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