miR-31 from adipose stem cell-derived extracellular vesicles promotes recovery of neurological function after ischemic stroke by inhibiting TRAF6 and IRF5

Abstract Stem cell therapy is emerging as a promising treatment option to restore a neurological function after ischemic stroke. Despite the growing number of candidate stem cell types, each with unique characteristics, there is a lack of experimental platform to systematically evaluate their neurorestorative potential. When stem cells are transplanted into ischemic brain, the therapeutic efficacy primarily depends on the response of the neurovascular unit (NVU) to these extraneous cells. In this work, we developed an ischemic stroke microphysiological system (MPS) with a functional NVU on a microfluidic chip. Our new chip design facilitated the incorporated cells to form a functional blood-brain barrier (BBB) and restore their in vivo-like behaviors in both healthy and ischemic conditions. We utilized this MPS to track the transplanted stem cells and characterize their neurorestorative behaviors reflected in gene expression levels. Each type of stem cells showed unique neurorestorative effects, primarily through supporting the endogenous recovery, rather than through direct cell replacement. And the recovery of synaptic activities, critical for neurological function, was more tightly correlated with the recovery of the structural and functional integrity in NVU, rather than with the regeneration of neurons itself.

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Thermoresponsive Gel Embedded with Adipose Stem-Cell-Derived Extracellular Vesicles Promotes Esophageal Fistula Healing in a Thermo-Actuated Delivery Strategy

ACS Nano ◽

10.1021/acsnano.8b00117 ◽

2018 ◽

Vol 12 (10) ◽

pp. 9800-9814 ◽

Cited By ~ 19

Author(s):

Amanda K. A. Silva ◽

Silvana Perretta ◽

Guillaume Perrod ◽

Laetitia Pidial ◽

Véronique Lindner ◽

...

Keyword(s):

Stem Cell ◽

Extracellular Vesicles ◽

Esophageal Fistula ◽

Adipose Stem Cell ◽

Delivery Strategy ◽

Fistula Healing ◽

Thermoresponsive Gel

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Screening and Functional Pathway Analysis of Pulmonary Genes Associated with Suppression of Allergic Airway Inflammation by Adipose Stem Cell-Derived Extracellular Vesicles

Stem Cells International ◽

10.1155/2020/5684250 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Sung-Dong Kim ◽

Shin Ae Kang ◽

Yong-Wan Kim ◽

Hak Sun Yu ◽

Kyu-Sup Cho ◽

...

Keyword(s):

Stem Cell ◽

Airway Inflammation ◽

Extracellular Vesicles ◽

Pathway Analysis ◽

Kegg Pathway ◽

Allergic Airway Inflammation ◽

Formyl Peptide Receptor ◽

Paraoxonase 1 ◽

Adipose Stem Cell ◽

Kegg Pathway Analysis

Background. Although mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) are as effective as MSCs in the suppression of allergic airway inflammation, few studies have explored the molecular mechanisms of MSC-derived EVs in allergic airway diseases. The objective of this study was to evaluate differentially expressed genes (DEGs) in the lung associated with the suppression of allergic airway inflammation using adipose stem cell- (ASC-) derived EVs. Methods. C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of ASC-derived EVs on allergic airway inflammation, 10 μg/50 μL of EVs were administered intranasally prior to OVA challenge. Lung tissues were removed and DEGs were compared pairwise among the three groups. DEG profiles and hierarchical clustering of the identified genes were analyzed to evaluate changes in gene expression. Real-time PCR was performed to determine the expression levels of genes upregulated after treatment with ASC-derived EVs. Enrichment analysis based on the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed to further identify the function of DEGs. Results. Expression of paraoxonase 1 (PON1), brain-expressed X-linked 2 (Bex2), insulin-like growth factor binding protein 6 (Igfbp6), formyl peptide receptor 1 (Fpr1), and secretoglobin family 1C member 1 (Scgb1c1) was significantly increased in asthmatic mice following treatment with ASC-derived EVs. GO enrichment and KEGG pathway analysis showed that these genes were strongly associated with immune system processes and their regulation, cellular processes, single-organism processes, and biological regulation. Conclusion. These results suggest that the DEGs identified in this study (PON1, Bex2, Igfbp6, Fpr1, and Scgb1c1) may be involved in the amelioration of allergic airway inflammation by ASC-derived EVs.

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Adipose Stem Cell-Derived Extracellular Vesicles Induce Proliferation of Schwann Cells via Internalization

Cells ◽

10.3390/cells9010163 ◽

2020 ◽

Vol 9 (1) ◽

pp. 163 ◽

Cited By ~ 6

Author(s):

Maximilian Haertinger ◽

Tamara Weiss ◽

Anda Mann ◽

Annette Tabi ◽

Victoria Brandel ◽

...

Keyword(s):

Image Analysis ◽

Stem Cell ◽

Extracellular Vesicles ◽

Live Cell Imaging ◽

Cell Imaging ◽

Live Cell ◽

Automated Image Analysis ◽

Dependent Manner ◽

Adipose Stem Cell ◽

Silica Beads

Recent studies showed a beneficial effect of adipose stem cell-derived extracellular vesicles (ADSC-EVs) on sciatic nerve repair, presumably through Schwann cell (SC) modulation. However, it has not yet been elucidated whether ADSC-EVs exert this supportive effect on SCs by extracellular receptor binding, fusion to the SC membrane, or endocytosis mediated internalization. ADSCs, ADSC-EVs, and SCs were isolated from rats and characterized according to associated marker expression and properties. The proliferation rate of SCs in response to ADSC-EVs was determined using a multicolor immunofluorescence staining panel followed by automated image analysis. SCs treated with ADSC-EVs and silica beads were further investigated by 3-D high resolution confocal microscopy and live cell imaging. Our findings demonstrated that ADSC-EVs significantly enhanced the proliferation of SCs in a time- and dose-dependent manner. 3-D image analysis revealed a perinuclear location of ADSC-EVs and their accumulation in vesicular-like structures within the SC cytoplasm. Upon comparing intracellular localization patterns of silica beads and ADSC-EVs in SCs, we found striking resemblance in size and distribution. Live cell imaging visualized that the uptake of ADSC-EVs preferentially took place at the SC processes from which the EVs were transported towards the nucleus. This study provided first evidence for an endocytosis mediated internalization of ADSC-EVs by SCs and underlines the therapeutic potential of ADSC-EVs in future approaches for nerve regeneration.

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

International Journal of Molecular Sciences ◽

10.3390/ijms222312860 ◽

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.

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Embryonic Stem Cell Derived Small Extracellular Vesicles Modulate Regulatory T Cells to Protect against Ischemic Stroke

ACS Nano ◽

10.1021/acsnano.1c00672 ◽

2021 ◽

Vol 15 (4) ◽

pp. 7370-7385

Author(s):

Yuguo Xia ◽

Guowen Hu ◽

Yu Chen ◽

Ji Yuan ◽

Juntao Zhang ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Ischemic Stroke ◽

Regulatory T Cells ◽

Embryonic Stem Cell ◽

Extracellular Vesicles ◽

Embryonic Stem

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Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.628908 ◽

2021 ◽

Vol 15 ◽

Author(s):

Xi-Le Zhang ◽

Xiao-Guang Zhang ◽

Yan-Ran Huang ◽

Yan-Yan Zheng ◽

Peng-Jie Ying ◽

...

Keyword(s):

Systematic Review ◽

Stem Cell ◽

Ischemic Stroke ◽

Animal Models ◽

Confidence Interval ◽

Stem Cell Transplantation ◽

Effect Size ◽

Infarct Volume ◽

Neurological Function ◽

Cell Based Therapy

Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, −3.37; 95% confidence interval, −3.83 to −2.90) and infarct volume (effect size, −11.37; 95% confidence interval, −12.89 to −9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.

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