Mechanism of Human Umbilical Cord Mesenchymal Stem Cells Derived-Extracellular Vesicle in Cerebral Ischemia-Reperfusion
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ORIGINAL PAPER
Mechanism of Human Umbilical Cord Mesenchymal Stem Cells Derived-Extracellular Vesicle in Cerebral Ischemia-Reperfusion Injury Wenlei Wang1 · Zhen Ji1 · Chunyan Yuan2 · Yanfang Yang1 Received: 4 March 2020 / Revised: 9 November 2020 / Accepted: 11 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are implicated in cerebral ischemia reperfusion (I/R) injury process. In this study, after extraction and identification of human umbilical cord MSCs (HMCs)-derived EVs, I/R rat models were established and treated with HMC-EVs to measure pathological damage, apoptosis and inflammation in brain tissues. The differentially expressed microRNAs (miRs) in HMC-EVs and I/R rat tissues were screened. The downstream gene and pathways of miR-24 were analyzed. The gain- and loss-of function of miR-24 in HMC-EVs was performed in I/R rat models and hypoxia/reoxygenation (H/R) cell models. SH-SY5Y cells were subjected to hypoxia and biological behaviors were detected by MTT assay, colony formation experiment, EdU staining and Transwell assays, and cells were incubated with the inhibitors of downstream pathways. As expected, infarct size, brain tissue apoptosis and inflammation were decreased after HMC-EVs treatment. miR-24 overexpression in HMC-EVs reduced I/R injury, while miR-24 knockdown in HMC-EVs impaired the protective roles of HMC-EVs in I/R injury. HMC-EVs-carried miR-24 could target AQP4 to activate the P38 MAPK/ERK1/2/P13K/AKT pathway, and thus promoted the proliferation and migration of SH-SY5Y cells after H/R injury, which were reversed by LY294002 and PD98095. Taken together, HMC-EVs-carried miR-24 played protective roles in I/R injury, possibly by targeting AQP4 and activating the P38 MAPK/ERK1/2/P13K/AKT pathway. This study may offer novel perspective for I/R injury treatment. Keywords Cerebral ischemia reperfusion injury · Human umbilical cord mesenchymal stem cells · Extracellular vesicles · microRNA-24 · AQP4 · P38 MAPK/ERK1/2
Introduction Ischemia means the lack of blood supply for tissues owing to the obstruction of arterial inflow, while reperfusion, although essential to reconstruct the delivery of oxygen and nutrients to normalize cell metabolism, it may cause the pathogenic process, aggravate the damage caused by ischemia itself, and result in tissue damage in distant organs [1]. When cerebral blood flow is interrupted transiently, cerebral ischemia/reperfusion (I/R) injury occurs following oxygen and glucose * Yanfang Yang [email protected] 1
Department of Neurology, Qingdao Chengyang People’s Hospital, No. 600 Changcheng Road, Chengyang District, Qingdao 266109, Shandong, People’s Republic of China
Department of Rehabilitation Medicine, Qingdao Chengyang People’s Hospital, Qingdao 266109, Shandong, People’s Republic of China
2
deprivation. The resulting brain dysfunction leads to high rates of mortality and disability [2]. I/R injury is related to severe clinical manifestat
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