scholarly journals Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 767
Author(s):  
Courtney Davis ◽  
Sean I. Savitz ◽  
Nikunj Satani
Keyword(s):  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Culture Conditions ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
Inflammatory Molecules ◽  
The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

scholarly journals Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA

2021 ◽  
pp. 0271678X2199298
Author(s):  
Chao Li ◽  
Chunyang Wang ◽  
Yi Zhang ◽  
Owais K Alsrouji ◽  
Alex B Chebl ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Therapeutic Effects ◽  
Vessel Occlusion ◽  
Healthy Human ◽  
Stroke Treatment

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.

Can the Use of Oral Minocycline Improve Ischemic Stroke Outcomes?

2008 ◽  
Vol 21 (2) ◽  
pp. 159-164
Author(s):  
Kathy B. Lee
Keyword(s):  
United States ◽  
Ischemic Stroke ◽  
The United States ◽  
Sudden Onset ◽  
Pharmacological Agents ◽  
Stroke Outcomes ◽  
Stroke Treatment ◽  
The Brain ◽  
Brain Ischemic Stroke

Cerebrovascular accident (CVA), also known as ischemic stroke, is the sudden onset of neurologic deficit attributable to a focal vascular cause.1 It is the third leading cause of death, with the death rate being reported as 50.0 (per 100,000 population) in the United States in 2004.2 It is also a leading cause for serious, long-term disability in the United States. While there are various causes, the large majority of strokes result from either global or focal ischemia of the brain. Ischemic stroke accounts for 87% of all strokes, while intracerebral and subarachnoid hemorrhage makes up the remainder. 2 Currently, the primary pharmacological agents used in stroke treatment are thrombolytics, not without limitations, however, and antiplatelet therapy. 3 Minocycline, a semisynthetic tetracycline antibiotic, has recently gained attention as a neuroprotective agent. A recent study evaluated the use of minocycline in the treatment of acute stroke and demonstrated promising results.4 A review of the mechanisms of action and data presented in past studies will be examined to evaluate the efficacy and clinical impact of minocycline in the treatment of acute ischemic stroke.

scholarly journals Neuroprotection from Stem Cell-Derived Human Adipose Extracellular Vesicles Intranasally Administered 24 Hours After Stroke in Rats. 

2021 ◽  
Author(s):  
Francieli Rohden ◽  
Luciele Varaschini Teixeira ◽  
Luis Pedro Bernardi ◽  
Pâmela Lukasewicz ◽  
Mariana Colombo ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Infarct Volume ◽  
Human Adipose Tissue ◽  
Long Term Memory ◽  
Infarct Core ◽  
Infarct Zone ◽  
Stroke Treatment ◽  
Administration Routes

Abstract Ischemic stroke is a major cause of death and disability, demanding innovative and accessible therapeutic strategies. Approaches presenting an optimal period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. We evaluated the potential neuroprotective properties of nasally administered human adipose tissue stem cells (hAT-MSCs)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. A single intranasal EV (200 µg/kg) was administered 24 h after a focal permanent ischemic stroke in rats. A higher tropism of EVs was observed in the peri-infarct zone surrounding the infarct core. In the same brain region, there was a significant decrease in the infarct volume, improvement of the blood-brain barrier, and re-stabilization of vascularization. In addition, EVs recovered the impairment of long-term motor and behavioral performance induced by an ischemic stroke. Surprisingly, one single intranasal EVs administration reestablished: i) front paws symmetry, ii) short- and long-term memory, and iii) anxiety-like behavior. In line with the findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

scholarly journals Potential Role of Exosomes in Ischemic Stroke Treatment

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 115
Author(s):  
Lingling Jiang ◽  
Weiqi Chen ◽  
Jinyi Ye ◽  
Yilong Wang
Keyword(s):  
Ischemic Stroke ◽  
Positive Impact ◽  
Current Knowledge ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
Neuroprotective Drugs ◽  
Life Threatening ◽  
Low Toxicity ◽  
Neurovascular Remodeling

Ischemic stroke is a life-threatening cerebral vascular disease and accounts for high disability and mortality worldwide. Currently, no efficient therapeutic strategies are available for promoting neurological recovery in clinical practice, except rehabilitation. The majority of neuroprotective drugs showed positive impact in pre-clinical studies but failed in clinical trials. Therefore, there is an urgent demand for new promising therapeutic approaches for ischemic stroke treatment. Emerging evidence suggests that exosomes mediate communication between cells in both physiological and pathological conditions. Exosomes have received extensive attention for therapy following a stroke, because of their unique characteristics, such as the ability to cross the blood brain–barrier, low immunogenicity, and low toxicity. An increasing number of studies have demonstrated positively neurorestorative effects of exosome-based therapy, which are largely mediated by the microRNA cargo. Herein, we review the current knowledge of exosomes, the relationships between exosomes and stroke, and the therapeutic effects of exosome-based treatments in neurovascular remodeling processes after stroke. Exosomes provide a viable and prospective treatment strategy for ischemic stroke patients.

scholarly journals Functional Recovery Caused by Human Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles Administered 24 h after Stroke in Rats

2021 ◽  
Vol 22 (23) ◽  
pp. 12860
Author(s):  
Francieli Rohden ◽  
Luciele Varaschini Teixeira ◽  
Luis Pedro Bernardi ◽  
Pamela Cristina Lukasewicz Ferreira ◽  
Mariana Colombo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Stem Cell ◽  
Ischemic Stroke ◽  
Mesenchymal Stem Cell ◽  
Extracellular Vesicles ◽  
Infarct Volume ◽  
Human Adipose Tissue ◽  
Behavioral Impairment ◽  
Stroke Treatment

Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood–brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

scholarly journals Brain–kidney interaction: Renal dysfunction following ischemic stroke

2019 ◽  
Vol 40 (2) ◽  
pp. 246-262 ◽  
Author(s):  
Qiang Zhao ◽  
Tao Yan ◽  
Michael Chopp ◽  
Poornima Venkat ◽  
Jieli Chen
Keyword(s):  
Patient Outcome ◽  
Ischemic Stroke ◽  
Immune Responses ◽  
Observational Studies ◽  
Experimental Studies ◽  
Cerebral Injury ◽  
Mortality And Morbidity ◽  
The Brain

Stroke is a leading cause of mortality and morbidity, with long-term debilitating effects. Accumulating evidence from experimental studies as well as observational studies in patients suggests a cross talk between the brain and kidney after stroke. Stroke may lead to kidney dysfunction which can adversely impact patient outcome. In this review article, we discuss the epidemiology and mechanisms of brain–kidney interaction following ischemic stroke. Specifically, we discuss the role of the central autonomic network, autoregulation, inflammatory and immune responses, the role of extracellular vesicles and their cargo microRNA, in mediating brain–kidney interaction following stroke. Understanding the bidirectional nature of interaction between the brain and kidney after cerebral injury would have clinical implications for the treatment of stroke and overall patient outcome.

Neuroprotection of Extracellular Vesicles From Human Adipose Stem Cells Intranasally Administered 24 Hours After Stroke In Rats

2021 ◽  
Author(s):  
Francieli Rohden ◽  
Luciele Varaschini Teixeira ◽  
Luis Pedro Bernardi ◽  
Pâmela Cristina Lukasewicz Ferreira ◽  
Mariana Colombo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Human Adipose Tissue ◽  
Long Term Memory ◽  
Infarct Core ◽  
Infarct Zone ◽  
Stroke Treatment ◽  
Short And Long Term

Abstract Ischemic stroke is a prominent cause of death and disability, demanding for innovative and reachable therapeutic strategies. Thus, approaches presenting optimal period for therapeutic intervention and new routes of treatments administration as promising tools for stroke treatment. In this study, we evaluated the potential neuroprotective properties of nasally administration of human adipose tissue stem cells (hAT-MSC)-derived extracellular vesicles (EVs), obtained from healthy individuals submitted to liposuction. A single intranasal EVs (200 µg/Kg) administration performed 24 h after a focal permanent ischemic stroke in rats. Was observed a higher tropism of EVs by peri-infarct zone, surrounding the infarct core. Interestingly, in the same brain region, was observed a significant decrease in the volume of the infarct, improvement the blood-brain barrier and re-stabilization of vascularization. In addition, EVs recover the impairment on long-term motor and behavioral performance induced by ischemic stroke. Surprisingly, one single intranasal EVs administration reestablished: i) front paws symmetry; ii), short- and long-term memory; iii) anxiety-like behavior. In keeping with this, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy in stroke.

scholarly journals Extracellular vesicles from human adipose stem cells are neuroprotective after stroke in rats

2020 ◽  
Author(s):  
Francieli Rohden ◽  
Luciele Varaschini Teixeira ◽  
Luis Pedro Bernardi ◽  
Nicolly Paz Ferreira Marques ◽  
Mariana Colombo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Therapeutic Strategy ◽  
Human Adipose Tissue ◽  
Long Term Memory ◽  
Stroke Treatment ◽  
Short And Long Term ◽  
Human Adipose Stem Cells

ABSTRACTIschemic stroke is a prominent cause of death and disability, demanding innovative therapeutic strategies. Accordingly, extracellular vesicles (EVs) released from mesenchymal stem cells are promising tools for stroke treatment. In this study, we evaluated the potential neuroprotective properties of EVs released from human adipose tissue stem cells (hAT-MSC), which were obtained from a healthy individual submitted to liposuction. A single intranasal EVs administration was performed 24 h after the ischemic stroke in rats. The EVs brain penetration and the tropism to brain zone of ischemia was observed 18 h after administration. Thus, we measured EVs neuroprotection against the ischemic stroke-induced impairment on long-term motor and behavioral performance. Indeed, one single intranasal EVs administration reversed the stroke damages on: i) front paws symmetry; ii) working memory, short- and long-term memory; iii) anxiety-like behavior. These findings highlight hAT-MSC-derived EVs as a promising therapeutic strategy in stroke.

Long-term management of patients with multiple brain metastases after shaped beam radiosurgery

2004 ◽  
pp. 406-412
Author(s):  
Paul Okunieff ◽  
Michael C. Schell ◽  
Russell Ruo ◽  
E. Ronald Hale ◽  
Walter G. O'Dell ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tumor Control ◽  
Content Type ◽  
Negative Results ◽  
Multiple Metastases ◽  
Extracranial Disease ◽  
Successful Control ◽  
The Brain

✓ The role of radiosurgery in the treatment of patients with advanced-stage metastatic disease is currently under debate. Previous randomized studies have not consistently supported the use of radiosurgery to treat patients with numbers of brain metastases. In negative-results studies, however, intracranial tumor control was high but extracranial disease progressed; thus, patient survival was not greatly affected, although neurocognitive function was generally maintained until death. Because the future promises improved systemic (extracranial) therapy, the successful control of brain disease is that much more crucial. Thus, for selected patients with multiple metastases to the brain who remain in good neurological condition, aggressive lesion-targeting radiosurgery should be very useful. Although a major limitation to success of this therapy is the lack of control of extracranial disease in most patients, it is clear that well-designed, aggressive treatment substantially decreases the progression of brain metastases and also improves neurocognitive survival. The authors present the management and a methodology for rational treatment of a patient with breast cancer who has harbored 24 brain metastases during a 3-year period.

scholarly journals Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

2021 ◽  
Vol 22 (15) ◽  
pp. 7847
Author(s):  
Anthony Fringuello ◽  
Philip D. Tatman ◽  
Tadeusz Wroblewski ◽  
John A. Thompson ◽  
Xiaoli Yu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Hemorrhagic Stroke ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Interleukin 7 ◽  
Poor Outcomes ◽  
Patient Prognosis ◽  
The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

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