Role of Exosomes Derived from miR-133b Modified MSCs in an Experimental Rat Model of Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) has poor outcomes due to high mortality and morbidity, but until now, the effective treatments remain limited. MicroRNAs (miRNAs) are vital regulators of gene expression and demonstrated to be linked to the pathogenesis of various central nervous system (CNS) diseases. Exosomes are considered as cell-to-cell communication vectors and secreted largely by mesenchymal stromal cells (MSCs). The present study investigated the role of miR-133b delivered by exosomes secreted from MSCs to brain tissues in rats after ICH. An autologous arterial blood ICH model in adult male Sprague-Dawley (SD) rats was used in this study. At 72 h after transfection with miR-133b mimics in MSCs, miR-133b-modified MSC-derived exosomes were collected from medium of MSCs and then injected to rats via tail vein. The levels of miR-133b in secreted exosomes and brain tissues of rats in various groups and the levels of RhoA, phosphorylations of extracellular signal regulating kinase (ERK1/2), and cAMP response element-binding protein (CREB) were detected by real-time PCR and western blot analysis, respectively. The effects of miR-133b on neuronal apoptosis and degeneration were respectively evaluated by TUNEL and fluoro-jade B staining. The miR-133b levels were reduced in brain tissues of rats at 24 h and peaked at 72 h after ICH. At 24 h after miR-133b-modified exosome administration, the level of miR-133b was significantly increased, while the apoptotic and neurodegenerative neurons were obviously reduced in brain tissues after ICH. The results of western blot analysis showed that miR-133b modified exosomes treatment remarkably suppressed RhoA expression and activated ERK1/2/CREB in brain tissues after ICH. Collectively, our investigation suggested that exosomes derived from miR-133b modified MSCs exhibited neuroprotective role for anti-apoptotic effect of miR-133b mediating RhoA and ERK1/2/CREB in rats after ICH.

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

“…Exosomes are a newly described mechanism of intercellular communication facilitating transfer of miRNAs, lipids, mRNAs, and proteins [36]. Importantly, exosome delivers miRNA or protein to the brain [25,37]. Furthermore, modified exosomes with RVG fused to membrane glycoprotein Lamp2b efficiently delivered miRNA to the brain [34].…”

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…[ 193 ] Additionally, EVs from miR‐133b overexpressing MSCs showed an anti‐apoptotic and neuroprotective ability in an intracerebral hemorrhage rat model. [ 194 ] Hypoxia inducible factor (HIF)‐1α overexpression yielded MSC‐CM that enhanced endothelial cell migration, [ 195 ] while HIF‐1α MSC‐EVs enhanced angiogenesis in vitro and in vivo, mediated by EV‐shuttled Jagged 1, [ 196 ] and promoted bone regeneration in a rabbit model of avascular necrosis of the femoral head. [ 197 ] Cartilage tissue regeneration in an osteoarthritis rat model was promoted by delivery of EVs secreted from miR‐140‐5p‐overexpressing MSCs that enhanced cell migration and proliferation.…”

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent

“…These authors also demonstrated that astrocytes treated with exosomes derived from miR-133b-overexpressing MSCs increased neurite branching, and elongation of cortical embryonic rat neurons in vivo [145]. Moreover, exosomes from miR-133b-overexpressing MSCs also suppressed RhoA expression and activated ERK1, ERK2, and CREB in brain tissues in an intracerebral hemorrhage rat model, which resulted in attenuation of apoptosis and neurodegeneration [146]. In other experiments, exosomes from miR-30d-5p-overexpressing MSCs suppressed autophagy by promoting M2 polarization of microglia and macrophages, which reversed brain injury induced by acute ischemic stroke and autophagy in an MCAO mouse model [140].…”