Extracellular vesicles derived from human Wharton’s jelly mesenchymal stem cells protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers

Abstract Background Mesenchymal stem cells (MSCs) have been explored as promising tools for treatment of several neurological and neurodegenerative diseases. MSCs release abundant extracellular vesicles (EVs) containing a variety of biomolecules, including mRNAs, miRNAs, and proteins. We hypothesized that EVs derived from human Wharton’s jelly would act as mediators of the communication between hMSCs and neurons and could protect hippocampal neurons from damage induced by Alzheimer’s disease-linked amyloid beta oligomers (AβOs). Methods We isolated and characterized EVs released by human Wharton’s jelly mesenchymal stem cells (hMSC-EVs). The neuroprotective action of hMSC-EVs was investigated in primary hippocampal cultures exposed to AβOs. Results hMSC-EVs were internalized by hippocampal cells in culture, and this was enhanced in the presence of AβOs in the medium. hMSC-EVs protected hippocampal neurons from oxidative stress and synapse damage induced by AβOs. Neuroprotection by hMSC-EVs was mediated by catalase and was abolished in the presence of the catalase inhibitor, aminotriazole. Conclusions hMSC-EVs protected hippocampal neurons from damage induced by AβOs, and this was related to the transfer of enzymatically active catalase contained in EVs. Results suggest that hMSC-EVs should be further explored as a cell-free therapeutic approach to prevent neuronal damage in Alzheimer’s disease.

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Faculty Opinions recommendation of Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer's disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727138175.793569267 ◽

2020 ◽

Author(s):

Filippo Milano

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cognitive Function ◽

Umbilical Cord ◽

Hippocampal Neurogenesis ◽

Human Umbilical Cord ◽

Stem Cells Transplantation

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Intracerebral Injection of Extracellular Vesicles from Mesenchymal Stem Cells Exerts Reduced Aβ Plaque Burden in Early Stages of a Preclinical Model of Alzheimer’s Disease

Cells ◽

10.3390/cells8091059 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1059 ◽

Cited By ~ 13

Author(s):

Chiara A. Elia ◽

Matteo Tamborini ◽

Marco Rasile ◽

Genni Desiato ◽

Sara Marchetti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Clinical Manifestations ◽

Plaque Burden ◽

Intracerebral Injection ◽

Early Stages ◽

Β Amyloid

Bone marrow Mesenchymal Stem Cells (BM-MSCs), due to their strong protective and anti-inflammatory abilities, have been widely investigated in the context of several diseases for their possible therapeutic role, based on the release of a highly proactive secretome composed of soluble factors and Extracellular Vesicles (EVs). BM-MSC-EVs, in particular, convey many of the beneficial features of parental cells, including direct and indirect β-amyloid degrading-activities, immunoregulatory and neurotrophic abilities. Therefore, EVs represent an extremely attractive tool for therapeutic purposes in neurodegenerative diseases, including Alzheimer’s disease (AD). We examined the therapeutic potential of BM-MSC-EVs injected intracerebrally into the neocortex of APPswe/PS1dE9 AD mice at 3 and 5 months of age, a time window in which the cognitive behavioral phenotype is not yet detectable or has just started to appear. We demonstrate that BM-MSC-EVs are effective at reducing the Aβ plaque burden and the amount of dystrophic neurites in both the cortex and hippocampus. The presence of Neprilysin on BM-MSC-EVs, opens the possibility of a direct β-amyloid degrading action. Our results indicate a potential role for BM-MSC-EVs already in the early stages of AD, suggesting the possibility of intervening before overt clinical manifestations.

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CHIP Reverses Hyperglycemia-associated PTEN Stability in Wharton's Jelly Derived Mesenchymal Stem Cells and Promotes Its Therapeutic Potential Against Diabetes-induced Cardiac Injury

10.21203/rs.3.rs-165217/v1 ◽

2021 ◽

Author(s):

Ayaz Ali ◽

Wei-Wen Kuo ◽

Chia-Hua Kuo ◽

Jeng-Feng Lo ◽

Ray-Jade Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cardiac Injury ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Downstream Signaling ◽

Wharton's Jelly ◽

Induced Apoptosis ◽

And Oxidative Stress

Abstract BackgroundRecent studies indicate that umbilical cord stem cells are cytoprotective against several disorders. One critical limitation in using stem cells is reduction in their viability under stressful conditions, such as diabetes. However, the molecular intricacies responsible for diabetic conditions are not fully elucidated.MethodsEffects of HG on Wharton's jelly derived mesenchymal stem cells (WJMSCs) viability was evaluated by MTT assay and flow cytometry. The mechanism responsible for HG-induced PTEN degradation was assessed using loss and gain of function, immunofluorescence, co-immunoprecipitation, and western blot analysis. Co-culturing of CHIP-overexpressed WJMSCs with embryo derived cardiomyoblasts was performed to analyze their ameliorative effects. The therapeutic effects of CHIP expressing WJMSCs were further validated in Sprague Dawley male (eight weeks old) STZ-induced diabetic animals by echocardiography, immunohistochemistry, hematoxylin eosin, and masson’s trichrome and TUNEL staining. Multiple comparisons were accessed through one‐way ANOVA and p-Value of <0.05 was considered statistically signiﬁcant. ResultsIn this study, we found that high glucose (HG) conditions induced loss of chaperone homeostasis, stabilized PTEN, triggered the downstream signaling cascade, and induced apoptosis and oxidative stress in Wharton's jelly derived mesenchymal stem cells (WJMSCs). Increased CHIP expression promoted PTEN degradation via the ubiquitin-proteasome system and shortened its half-life during HG stress. Docking studies confirmed the interaction of CHIP with PTEN and FOXO3a with the Bim promoter region. Further, it was found that the chaperone system is involved in CHIP-mediated PTEN proteasomal degradation. CHIP depletion stabilizes PTEN whereas PTEN inhibition showed an inverse effect. CHIP overactivation suppressed the binding of FOXO3a with bim. Co-culturing CHIP overexpressed WJMSCs suppressed HG-induced apoptosis and oxidative stress in cardiac cells. Finally, CHIP overexpression and PTEN inhibition minimized blood glucose levels, improved body and heart weight, and rescued hyperglycemia-induced cardiac injury in diabetic rats. ConclusionThe current study suggests that CHIP confers resistance to apoptosis and oxidative stress and modulates PTEN and the downstream signaling cascade by promoting PTEN proteasomal degradation, thereby potentially exerting therapeutic effects against diabetes-induced cardiomyopathies.

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Development of injectable graphene oxide/laponite/gelatin hydrogel containing Wharton's jelly mesenchymal stem cells for treatment of oxidative stress-damaged cardiomyocytes

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2021.112150 ◽

2022 ◽

Vol 209 ◽

pp. 112150

Author(s):

Yung-Hsin Cheng ◽

Shih-Jen Cheng ◽

Hsin-Ho Chen ◽

Wei-Chia Hsu

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Graphene Oxide ◽

Wharton’S Jelly ◽

Wharton's Jelly ◽

Gelatin Hydrogel

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Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers

Journal of Biological Chemistry ◽

10.1074/jbc.m117.807180 ◽

2017 ◽

Vol 293 (6) ◽

pp. 1957-1975 ◽

Cited By ~ 45

Author(s):

Mariana A. de Godoy ◽

Leonardo M. Saraiva ◽

Luiza R. P. de Carvalho ◽

Andreia Vasconcelos-dos-Santos ◽

Hellen J. V. Beiral ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Hippocampal Neurons ◽

Amyloid Β

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Oxidative Stress in Alzheimer’s Disease: In Vitro Therapeutic Effect of Amniotic Fluid Stem Cells Extracellular Vesicles

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/2785343 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Martina Gatti ◽

Manuela Zavatti ◽

Francesca Beretti ◽

Daniela Giuliani ◽

Eleonora Vandini ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Amniotic Fluid ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Amniotic Fluid Stem Cells ◽

Vitro Model

Alzheimer’s disease (AD) is characterized by abnormal protein aggregation, deposition of extracellular β-amyloid proteins (Aβ), besides an increase of oxidative stress. Amniotic fluid stem cells (AFSCs) should have a therapeutic potential for neurodegenerative disorders, mainly through a paracrine effect mediated by extracellular vesicles (EV). Here, we examined the effect of EV derived from human AFSCs (AFSC-EV) on the disease phenotypes in an AD neuron primary culture. We observed a positive effect of AFSC-EV on neuron morphology, viability, and Aβ and phospho-Tau levels. This could be due to the apoptotic and autophagic pathway modulation derived from the decrease in oxidative stress. Indeed, reactive oxygen species (ROS) were reduced, while GSH levels were enhanced. This modulation could be ascribed to the presence of ROS regulating enzymes, such as SOD1 present into the AFSC-EV themselves. This study describes the ROS-modulating effects of extracellular vesicles alone, apart from their deriving stem cell, in an AD in vitro model, proposing AFSC-EV as a therapeutic tool to stop the progression of AD.

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