Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis
Abstract 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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-020-02091-x |
| _version_ | 1818326796669550592 |
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| author | Yamei Zhang Junying Liu Mi Su Xin Wang Chenchen Xie |
| author_facet | Yamei Zhang Junying Liu Mi Su Xin Wang Chenchen Xie |
| author_sort | Yamei Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-13T12:06:04Z |
| format | Article |
| id | doaj.art-6b7ebabf7626482a8e78b22e311157da |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-13T12:06:04Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-6b7ebabf7626482a8e78b22e311157da2022-12-21T23:46:57ZengBMCStem Cell Research & Therapy1757-65122021-02-0112111510.1186/s13287-020-02091-xExosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axisYamei Zhang0Junying Liu1Mi Su2Xin Wang3Chenchen Xie4Clinical Genetics Laboratory, Affiliated Hospital & Clinical Medical College of Chengdu UniversityClinical Genetics Laboratory, Affiliated Hospital & Clinical Medical College of Chengdu UniversityClinical Genetics Laboratory, Affiliated Hospital & Clinical Medical College of Chengdu UniversityClinical Genetics Laboratory, Affiliated Hospital & Clinical Medical College of Chengdu UniversityDepartment of Neurology, Affiliated Hospital of Chengdu UniversityAbstract 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.https://doi.org/10.1186/s13287-020-02091-xAdipose-derived mesenchymal stem cellsIschemia-reperfusionExtracellular vesiclesmicroRNA-22-3pKDM6BBMP2 |
| spellingShingle | Yamei Zhang Junying Liu Mi Su Xin Wang Chenchen Xie Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis Stem Cell Research & Therapy Adipose-derived mesenchymal stem cells Ischemia-reperfusion Extracellular vesicles microRNA-22-3p KDM6B BMP2 |
| 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 | Adipose-derived mesenchymal stem cells Ischemia-reperfusion Extracellular vesicles microRNA-22-3p KDM6B BMP2 |
| url | https://doi.org/10.1186/s13287-020-02091-x |
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