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

Abstract

Background

MicroRNAs (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).

Methods

The 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.

Results

LCN2 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.

Conclusion

BMSCs-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.