Role of Exosomes Derived from miR-133b Modified MSCs in an Experimental Rat Model of Intracerebral Hemorrhage
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.
KeywordsExosome MiR-133b Mesenchymal stromal cells ICH Apoptosis
Central nervous system
Mesenchymal stromal cells
Extracellular signal regulating kinase
cAMP response element-binding protein
Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
Secondary brain injury
Reactive oxygen species
Spinal cord injury
Adipose-derived stem cells
Compliance with Ethical Standards
All animal experiments were approved by the Ethics Committee of the First Affiliated Hospital of Soochow University and were performed in accordance with the guidelines of the National Institutes of Health on the care and use of animals.
Conflict of Interest Statement
The authors declare that they have no competing interests.
- Otero-Ortega L, Gomez de Frutos MC, Laso-Garcia F, Rodriguez-Frutos B, Medina-Gutierrez E, Lopez JA, Vazquez J, Diez-Tejedor E, Gutierrez-Fernandez M (2017) Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab. 271678X17708917Google Scholar
- Wang Z, Chen Z, Yang J, Yang Z, Yin J, Zuo G, Duan X, Shen H, Li H, Chen G (2017) Identification of two phosphorylation sites essential for annexin A1 in blood-brain barrier protection after experimental intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 37:2509–2525CrossRefPubMedGoogle Scholar
- Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M (2013b) MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 31:2737–2746CrossRefPubMedPubMedCentralGoogle Scholar
- Xin H, Wang F, Li Y, Lu QE, Cheung WL, Zhang Y, Zhang ZG, Chopp M (2017) Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant 26:243–257CrossRefPubMedPubMedCentralGoogle Scholar
- Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y (2015) Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 122:856–867CrossRefPubMedPubMedCentralGoogle Scholar