Exosomes derived from microRNA-138-5p-overexpressing bone marrow-derived mesenchymal stem cells confer neuroprotection to astrocytes following ischemic stroke via inhibition of LCN2

Yiming Deng,Feng Gao,Duanduan Chen,Xuan Sun,Lian Liu,Jingbo Zhang,Zhongrong Miao,Ligang Song,Dapeng Mo,Ning Ma,Hong Lv,Xiaochuan Huo,Tianyi Yan,Guojun Zhang

doi:10.1186/s13036-019-0193-0

Abstract

BackgroundMicroRNAs (miRNAs) are implicated in the progression of ischemic stroke (IS) and bone marrow-derived mesenchymal stem cells (BMSCs)-derived exosomes play a role in IS therapy. Herein we hypothesized that the BMSCs-derived exosomes containing overexpressed miR-138-5p could protect the astrocytes following IS involved with lipocalin 2 (LCN2).MethodsThe differentially expressed gene related to IS was initially identified by bioinformatics analysis. miR-138-5p was predicted to regulate LCN2. The expression of miR-138-5p and LCN2 was altered in the oxygen-glucose deprivation (OGD)-induced astrocytes. Furthermore, the cell behaviors and inflammatory responses were evaluated both in astrocytes alone and astrocytes co-cultured with exosomes derived from BMSCs overexpressing miR-138-5p to explore the involvement of miR-138-5p and LCN2 in IS. Besides, middle cerebral artery occlusion (MCAO) mouse model was established to explore the effect of BMSCs-derived exosomal miR-138-5p in IS in vivo.ResultsLCN2 was highly expressed in IS. Besides, LCN2 was a target gene of miR-138-5p. BMSCs-derived exosomes could be endocytosed by astrocytes via co-culture. Overexpression of miR-138-5p promoted the proliferation and inhibited apoptosis of astrocytes injured by OGD, accompanied by the reduced expression of inflammatory factors, which was achieved by down-regulating LCN2. More importantly, BMSCs delivered miR-138-5p to the astrocytes via exosomes and BMSCs-derived exosomal miR-138-5p alleviated neuron injury in IS mice.ConclusionBMSCs-derived exosomal miR-138-5p reduces neurological impairment by promoting proliferation and inhibiting inflammatory responses of astrocytes following IS by targeting LCN2, which may provide a novel target for IS treatment.

Highlights

Stroke remains the second leading contributor to the progressive increase observed in global deaths and disability
lipocalin 2 (LCN2) is highly expressed in ischemic stroke (IS) and may affect the OGDinduced astrocytes Initially, the IS-related expression profiles GSE30655 and GSE35338 were retrieved from the Gene Expression Omnibus (GEO) database
In an attempt to elucidate the regulatory effect of LCN2 on astrocytes under oxygen-glucose deprivation (OGD) conditions, the oxygenglucose deprived astrocytes were treated with sh-LCN2NC and sh-LCN2

Summary

Introduction

Stroke remains the second leading contributor to the progressive increase observed in global deaths and disability. Inflammation is widely considered to exert a drastic effect on the pathogenesis of IS as it may lead to ischemic brain injury [4]. Astrocytic inflammation, a consequence of stroke, can aggravate ischemic lesions, while astrocytes can be conducive for neuroprotection [5]. Several improvements in the arena of IS treatment have been achieved, including astrocyte-based therapy discovered as one of the promising therapies [6]. Exosomes have been found as a promising endogenous drug delivery nanosystem for cerebral ischemia treatment [7]. It is of significance to further explore the novel treatment of IS based on exosomes endocytosed by astrocytes. MicroRNAs (miRNAs) are implicated in the progression of ischemic stroke (IS) and bone marrowderived mesenchymal stem cells (BMSCs)-derived exosomes play a role in IS therapy. We hypothesized that the BMSCs-derived exosomes containing overexpressed miR-138-5p could protect the astrocytes following IS involved with lipocalin 2 (LCN2)

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