The Exosomal MicroRNA Profile Is Responsible for the Mesenchymal Stromal Cell Transplantation-Induced Improvement of Functional Recovery after Stroke in Rats

Abstract

<b><i>Introduction:</i></b> The mechanism through which mesenchymal stromal cells (MSCs) enhance functional recovery in experimental models of stroke remains to be elucidated. This study was carried out to determine the microRNA (miRNA) profile elicited in response to MSC transplantation after stroke. <b><i>Methods:</i></b> This was an in vivo study on the effect of MSC transplantation on the exosomal miRNA profile in a rat model of middle cerebral artery occlusion (MCAO)-induced stroke. Eighteen male Sprague-Dawley rats were subjected to MCAO surgery (model group), and half received a transplantation of MSCs (model + MSC group) isolated from rat bone marrow. A sham-operated group (Sham) was included as a control. After 7 days, the volume of the brain lesion and severity of the functional impairments were measured. Exosomes were isolated from blood plasma samples for miRNA transcriptome analysis by Illumina sequencing. <b><i>Results:</i></b> The MCAO surgery successfully induced infarcts and neurological deficits in the rats, whereas the MSC transplantation significantly repaired these impairments. Illumina sequencing identified 764 known miRNAs, including 135 that were differentially expressed in common between the model + MSC and model, model and Sham, and model + MSC and Sham groups, respectively. Gene Ontology enrichment analysis revealed that the target genes of these miRNAs were associated with biological processes relevant to learning or memory and the development of the central and peripheral nervous systems. Pathway enrichment analysis identified a cluster of miRNAs (e.g., rno-miR-19b-3p, rno-miR-204-3p, rno-miR-125a-5p, rno-miR-672-3p, and rno-miR-667-3p) to be significantly related to the Janus kinase-signal transducer and activator of transcription, mechanistic target of rapamycin, phosphoinositide 3-kinases–Akt, and insulin signaling pathways via their control of their gene targets. <b><i>Conclusion:</i></b> We confirmed that MSC transplantation repaired stroke-induced functional impairments in rats by regulating various pathways associated with nervous system protection and MSC differentiation through the deregulation of exosomal miRNAs.