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Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury, the most common form of stroke, has high mortality and often brings persistent and serious brain dysfunction among survivors. Administration of adipose-derived mesenchymal stem cells (ASCs) has been suggested to alleviate the I/R brain injury,...

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Autores principales: Zhang, Yamei, Liu, Junying, Su, Mi, Wang, Xin, Xie, Chenchen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863295/
https://www.ncbi.nlm.nih.gov/pubmed/33546766
http://dx.doi.org/10.1186/s13287-020-02091-x
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author Zhang, Yamei
Liu, Junying
Su, Mi
Wang, Xin
Xie, Chenchen
author_facet Zhang, Yamei
Liu, Junying
Su, Mi
Wang, Xin
Xie, Chenchen
author_sort Zhang, Yamei
collection PubMed
description BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury, the most common form of stroke, has high mortality and often brings persistent and serious brain dysfunction among survivors. Administration of adipose-derived mesenchymal stem cells (ASCs) has been suggested to alleviate the I/R brain injury, but the mechanism remains uncharacterized. Here, we aimed at investigating the mechanism of ASCs and their extracellular vesicles (EVs) in the repair of or protection from I/R injury. METHODS: We established the middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reperfusion (OGD/RP) neuron model. ASCs or ASC-derived EVs (ASC-EVs) were co-cultured with neurons. RT-qPCR and Western blot analyses determined microRNA (miRNA)-22-3p, BMP2, BMF, and KDM6B expression in neurons upon treatment with ASC-EVs. Bioinformatics analysis predicted the binding between miR-22-3p and KDM6B. Using gain- and loss-of-function methods, we tested the impact of these molecules on I/R injury in vivo and in vitro. RESULTS: Treatment with ASCs and ASC-derived EVs significantly alleviated the I/R brain injury in vivo, elevated neuron viability in vitro, and decreased apoptosis. Interestingly, miR-22-3p was upregulated in ASC-EVs, and treatment with EV-miR-22-3p inhibitor led to increased apoptosis and decreased neuronal. Of note, miR-22-3p bound to and inhibited KDM6B, as demonstrated by dual-luciferase reporter gene assay and Western blot assay. Overexpression of KDM6B enhanced apoptosis of neurons in the OGD/RP model, and KDM6B bound to BMB2 and promoted its expression by binding to BMP2. Silencing of BMF reduced infarct volume and apoptosis in the stroke model. CONCLUSION: Results support a conclusion that ASC-EV-derived miR-22-3p could alleviate brain ischemic injury by inhibiting KDM6B-mediated effects on the BMP2/BMF axis. These findings compelling indicate a novel treatment strategy for cerebral ischemic injury.
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spelling pubmed-78632952021-02-05 Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis Zhang, Yamei Liu, Junying Su, Mi Wang, Xin Xie, Chenchen Stem Cell Res Ther Research BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury, the most common form of stroke, has high mortality and often brings persistent and serious brain dysfunction among survivors. Administration of adipose-derived mesenchymal stem cells (ASCs) has been suggested to alleviate the I/R brain injury, but the mechanism remains uncharacterized. Here, we aimed at investigating the mechanism of ASCs and their extracellular vesicles (EVs) in the repair of or protection from I/R injury. METHODS: We established the middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reperfusion (OGD/RP) neuron model. ASCs or ASC-derived EVs (ASC-EVs) were co-cultured with neurons. RT-qPCR and Western blot analyses determined microRNA (miRNA)-22-3p, BMP2, BMF, and KDM6B expression in neurons upon treatment with ASC-EVs. Bioinformatics analysis predicted the binding between miR-22-3p and KDM6B. Using gain- and loss-of-function methods, we tested the impact of these molecules on I/R injury in vivo and in vitro. RESULTS: Treatment with ASCs and ASC-derived EVs significantly alleviated the I/R brain injury in vivo, elevated neuron viability in vitro, and decreased apoptosis. Interestingly, miR-22-3p was upregulated in ASC-EVs, and treatment with EV-miR-22-3p inhibitor led to increased apoptosis and decreased neuronal. Of note, miR-22-3p bound to and inhibited KDM6B, as demonstrated by dual-luciferase reporter gene assay and Western blot assay. Overexpression of KDM6B enhanced apoptosis of neurons in the OGD/RP model, and KDM6B bound to BMB2 and promoted its expression by binding to BMP2. Silencing of BMF reduced infarct volume and apoptosis in the stroke model. CONCLUSION: Results support a conclusion that ASC-EV-derived miR-22-3p could alleviate brain ischemic injury by inhibiting KDM6B-mediated effects on the BMP2/BMF axis. These findings compelling indicate a novel treatment strategy for cerebral ischemic injury. BioMed Central 2021-02-05 /pmc/articles/PMC7863295/ /pubmed/33546766 http://dx.doi.org/10.1186/s13287-020-02091-x Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zhang, Yamei
Liu, Junying
Su, Mi
Wang, Xin
Xie, Chenchen
Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
title Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
title_full Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
title_fullStr Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
title_full_unstemmed Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
title_short Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
title_sort exosomal microrna-22-3p alleviates cerebral ischemic injury by modulating kdm6b/bmp2/bmf axis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863295/
https://www.ncbi.nlm.nih.gov/pubmed/33546766
http://dx.doi.org/10.1186/s13287-020-02091-x
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