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

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.

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

10.21203/rs.3.rs-300710/v1 ◽

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.

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

10.21203/rs.3.rs-249331/v1 ◽

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.

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

10.1101/2020.11.18.388355 ◽

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.

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

Cells ◽

10.3390/cells10040767 ◽

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.

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Enhancing therapeutic effects and in vivo tracking of adipose tissue derived mesenchymal stem cells for liver injury using bioorthogonal click chemistry

Nanoscale ◽

10.1039/d0nr07272a ◽

2020 ◽

Author(s):

Naishun Liao ◽

Da Zhang ◽

Ming Wu ◽

Huang-Hao Yang ◽

Xiaolong Liu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Stem Cell ◽

Liver Injury ◽

Mesenchymal Stem Cell ◽

Liver Diseases ◽

Therapeutic Effects

Adipose tissue derived mesenchymal stem cell (ADSC)-based therapy is attractive for liver diseases, but the long-term therapeutic outcome is still far from satisfaction due to low hepatic engraftment efficiency of...

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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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x21992980 ◽

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.

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