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Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.

Recent laboratory findings suggest that it might be possible to promote cerebral plasticity and neurological recovery after stroke by use of exogenous pharmacological or cell-based treatments. Brain microvasculature and glial cells respond in concert to ischaemic stressors and treatment, creating an environment in which successful recovery can ensue. Neurons remote from and adjacent to the ischaemic lesion are enabled to sprout, and neural precursor cells that accumulate with cerebral microvessels in the perilesional tissue further stimulate brain plasticity and neurological recovery. These factors interact in a highly dynamic way, facilitating temporally and spatially orchestrated responses of brain networks. In view of the complexity of the systems involved, stroke treatments that stimulate and amplify these endogenous restorative mechanisms might also provoke unwanted side-effects. In experimental studies, adverse effects have been identified when neurorestorative treatments were administered to animals with severe associated illnesses, after thrombolysis with alteplase, and when therapies were initiated outside appropriate time windows. Balancing the opportunities and possible risks, we provide suggestions for the translation of restorative therapies from the laboratory to the clinic.

Traumatic brain injury（TBI） is one of the major causes of death and disability worldwide.No effective treatment has been identified from clinical trials.Compelling evidence exists that treatment with mesenchymal stem cells（MSCs） exerts a substantial therapeutic effect after experimental brain injury.In addition to their soluble factors,therapeutic effects of MSCs may be attributed to their generation and release of exosomes.Exosomes are endosomal origin small-membrane nano-sized vesicles generated by almost all cell types.Exosomes play a pivotal role in intercellular communication.Intravenous delivery of MSC-derived exosomes improves functional recovery and promotes neuroplasticity in rats after TBI.Therapeutic effects of exosomes derive from the exosome content,especially micro RNAs（mi RNAs）.mi RNAs are small non-coding regulatory RNAs and play an important role in posttranscriptional regulation of genes.Compared with their parent cells,exosomes are more stable and can cross the blood-brain barrier.They have reduced the safety risks inherent in administering viable cells such as the risk of occlusion in microvasculature or unregulated growth of transplanted cells.Developing a cell-free exosome-based therapy may open up a novel approach to enhancing multifaceted aspects of neuroplasticity and to amplifying neurological recovery,potentially for a variety of neural injuries and neurodegenerative diseases.This review discusses the most recent knowledge of exosome therapies for TBI,their associated challenges and opportunities.

Here, for the first time, we test a novel hypothesis that systemic treatment of stroke with exosomes derived from multipotent mesenchymal stromal cells (MSCs) promote neurovascular remodeling and functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) followed by tail vein injection of 100 μg protein from MSC exosome precipitates or an equal volume of vehicle phosphate-buffered saline (PBS) (n = 6/group) 24 hours later. Animals were killed at 28 days after stroke and histopathology and immunohistochemistry were employed to identify neurite remodeling, neurogenesis, and angiogenesis. Systemic administration of MSC-generated exosomes significantly improved functional recovery in stroke rats compared with PBS-treated controls. Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control. Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

Traumatic brain injury (TBI) and stroke stand as prominent causes of global disability and mortality. Treatment strategies for stroke and TBI are shifting from targeting neuroprotection toward cell-based neurorestorative strategy, aiming to augment endogenous brain remodeling, which holds considerable promise for the treatment of TBI and stroke. Compelling evidence underscores that the therapeutic effects of cell-based therapy are mediated by the active generation and release of exosomes from administered cells. Exosomes, endosomal derived and nano-sized extracellular vesicles, play a pivotal role in intercellular communication. Thus, we may independently employ exosomes to treat stroke and TBI. Systemic administration of mesenchymal stem cell (MSC) derived exosomes promotes neuroplasticity and neurological functional recovery in preclinical animal models of TBI and stroke. In this mini review, we describe the properties of exosomes and recent exosome-based therapies of TBI and stroke. It is noteworthy that the microRNA cargo within exosomes contributes to their therapeutic effects. Thus, we provide a brief introduction to microRNAs and insight into their key roles in mediating therapeutic effects. With the increasing knowledge of exosomes, researchers have “engineered” exosome microRNA content to amplify their therapeutic benefits. We therefore focus our discussion on the therapeutic benefits of recently employed microRNA-enriched engineered exosomes. We also discuss the current opportunities and challenges in translating exosome-based therapy to clinical applications.

We previously demonstrated that multipotent mesenchymal stromal cells (MSCs) that overexpress microRNA 133b (miR-133b) significantly improve functional recovery in rats subjected to middle cerebral artery occlusion (MCAO) compared with naive MSCs and that exosomes generated from naive MSCs mediate the therapeutic benefits of MSC therapy for stroke. Here we investigated whether exosomes isolated from miR-133b-overexpressing MSCs (Ex-miR-133b+) exert amplified therapeutic effects. Rats subjected to 2 h of MCAO were intra-arterially injected with Ex-miR-133b+, exosomes from MSCs infected by blank vector (Ex-Con), or phosphate-buffered saline (PBS) and were sacrificed 28 days after MCAO. Compared with the PBS treatment, both exosome treatment groups exhibited significant improvement of functional recovery. Ex-miR-133b+ treatment significantly increased functional improvement and neurite remodeling/brain plasticity in the ischemic boundary area compared with the Ex-Con treatment. Treatment with Ex-miR-133b+ also significantly increased brain exosome content compared with Ex-Con treatment. To elucidate mechanisms underlying the enhanced therapeutic effects of Ex-miR-133b+, astrocytes cultured under oxygen- and glucose-deprived (OGD) conditions were incubated with exosomes harvested from naive MSCs (Ex-Naive), miR-133b downregulated MSCs (Ex-miR-133b−), and Ex-miR-133b+. Compared with the Ex-Naive treatment, Ex-miR-133b+ significantly increased exosomes released by OGD astrocytes, whereas Ex-miR-133b− significantly decreased the release. Also, exosomes harvested from OGD astrocytes treated with Ex-miR-133b+ significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons compared with the exosomes from OGD astrocytes subjected to Ex-Con. Our data suggest that exosomes harvested from miR-133b-overexpressing MSCs improve neural plasticity and functional recovery after stroke with a contribution from a stimulated secondary release of neurite-promoting exosomes from astrocytes.

Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA-126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR-126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126 EC−/− ), and miR-126 knockout control (miR-126 fl/fl ) mice were subjected to distal middle cerebral artery occlusion (dMCAo) ( n  = 10/group). Cardiac hemodynamics and function were measured using transthoracic Doppler echocardiography. Mice were sacrificed at 28 days after dMCAo. WT mice subjected to stroke exhibited significantly decreased cardiac ejection fraction and increased myocyte hypertrophy, fibrosis as well as increased heart inflammation, infiltrating macrophages, and oxidative stress compared to non-stroke animals. Stroke significantly decreased serum and heart miR-126 expression and increased miR-126 target genes, vascular cell adhesion protein-1, and monocyte chemotactic protein-1 gene, and protein expression in the heart compared to non-stroke mice. MiR-126 EC−/− mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126 fl/fl stroke mice. Exosomes derived from endothelial cells of miR-126 EC−/− (miR-126 EC−/− EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR-126 fl/fl (miR-126 fl/fl -EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126 fl/fl -EC-Exo exhibited significantly decreased hypertrophy than with miR-126 EC−/− EC-Exo treatment. Ischemic stroke directly induces cardiac dysfunction. Decreasing miR-126 expression may contribute to cardiac dysfunction after stroke in mice.

There is a compelling need to develop cell and pharmacological therapeutic approaches to be administered beyond the hyperacute phase of stroke. These therapies capitalize on the capacity of the brain for neuroregeneration and neuroplasticity and are designed to reduce neurological deficits after stroke. This review provides an update of bone marrow–derived mesenchymal stem cells (MSCs) and select pharmacological agents in clinical use for other indications that promote the recovery process in the subacute and chronic phases after stroke. Among these agents are 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins), erythropoietin (EPO), and phosphodiesterase type 5 (PDE-5) inhibitors and nitric oxide (NO) donors. Both the MSCs and the pharmacologic agents potentiate brain plasticity and neurobehavioral recovery after stroke.

Stroke induces new myelinating oligodendrocytes that are involved in ischemic brain repair. Molecular mechanisms that regulate oligodendrogenesis have not been fully investigated. MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate gene expression. MiR-146a has been reported to regulate immune response, but the role of miR-146a in oligodendrocyte progenitor cells (OPCs) remains unknown. Adult Wistar rats were subjected to the right middle cerebral artery occlusion (MCAo). In situ hybridization analysis with LNA probes against miR-146a revealed that stroke considerably increased miR-146a density in the corpus callosum and subventricular zone (SVZ) of the lateral ventricle of the ischemic hemisphere. In vitro, overexpression of miR-146a in neural progenitor cells (NPCs) significantly increased their differentiation into O4 + OPCs. Overexpression of miR-146a in primary OPCs increased their expression of myelin proteins, whereas attenuation of endogenous miR-146a suppressed generation of myelin proteins. MiR-146a also inversely regulated its target gene-IRAK1 expression in OPCs. Attenuation of IRAK1 in OPCs substantially increased myelin proteins and decreased OPC apoptosis. Collectively, our data suggest that miR-146a may mediate stroke-induced oligodendrogenesis.

Waste clearance (WC) is an essential process for brain homeostasis, which is required for the proper and healthy functioning of all cerebrovascular and parenchymal brain cells. This review features our current understanding of brain WC, both within and external to the brain parenchyma. We describe the interplay of the blood-brain barrier (BBB), interstitial fluid (ISF), and perivascular spaces within the brain parenchyma for brain WC directly into the blood and/or cerebrospinal fluid (CSF). We also discuss the relevant role of the CSF and its exit routes in mediating WC. Recent discoveries of the glymphatic system and meningeal lymphatic vessels, and their relevance to brain WC are highlighted. Controversies related to brain WC research and potential future directions are presented.