Extracellular Vesicles Derived from Bone Mesenchymal Stem Cells Carrying circ_0000075 Relieves Cerebral Ischemic Injury by Competitively Inhibiting miR-218-5p and Up-regulating E3 Ubiquitin Ligase SMURF2

• Published in: Molecular neurobiology Vol. 60; no. 5; pp. 2801 - 2818
• Main Authors: Liu, Yue, Li, You-Ping, Xiao, Li-Min, Chen, Li-Ke, Zheng, Su-Yue, Zeng, Er-Ming, Xu, Chun-Hua
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-05-2023; Springer Nature B.V
• Subjects: Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Brain Injuries; Brain injury; Cell Biology; Cerebral blood flow; Extracellular Vesicles; Ischemia; Mesenchymal Stem Cells; Mice; MicroRNAs - genetics; miRNA; Neurobiology; Neurology; Neurons; Neurosciences; Reperfusion; Smad protein; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitination; circRNA_0000075; YY1 transcription factor; microRNA-218-5p; Bone marrow mesenchymal stem cells; Smad ubiquitination regulatory factor 2; Cerebral ischemic injury
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-022-03192-9

Extracellular vesicle (EV)–encapsulated circRNAs have the potential role in affecting brain disorders. However, the role of circ_0000075 in cerebral ischemic injury remains unclear. Here, we tried to investigate the mechanism of bone marrow mesenchymal stem cell (BMSC)–derived EVs carrying circ_0000075 in the control of cerebral ischemic injury. Initially, a mouse model with cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO), followed by the determination of circ_0000075 expression. Then, neurons were isolated and subjected to oxygen–glucose deprivation/reperfusion. BMSCs were isolated for extraction of EVs. The correlation among circ_0000075, microRNA (miR)-218-5p, and Smad ubiquitination regulatory factor 2 (SMURF2) was detected with their roles in cerebral ischemic injury analyzed in vivo and in vitro. circ_0000075 was down-regulated in MCAO mice and engineered RVG-EVs were internalized by neurons to up-regulate circ_0000075 expression. Treatment of RVG-circ_0000075-EVs reduced brain tissue damage, increased neuronal count, and significantly curtailed apoptosis rate, suppressing cerebral ischemic injury in vitro and in vivo. miR-218-5p was targeted by circ_0000075 in neurons, which promoted SMURF2 expression. A negative correlation between SMURF2 and transcriptional regulator Yin Yang 1 (YY1) was identified. In vitro experiments further proved that circ_ 00,000 75 could down-regulate the expression of YY1 through SMURF2, and finally relieving cerebral ischemic injury. Collectively, engineered EVs delivered circ_0000075 into brain tissues and increased circ_0000075 expression, which down-regulated miR-218-5p and up-regulated SMURF2, thus alleviating cerebral ischemic injury.