<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

Abstract

Introduction: Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality, and the effective therapies for ICH remain to be explored. Exosomes (Exos) have been found to play important roles in cell communication by transferring molecules, including microRNAs (miRNAs/ miRs). MiRNAs are critical regulators of genes involved in many various biological processes and have been demonstrated to aggravate or alleviate brain damages induced by ICH. The aim of the present study was to investigate the effect of Exos derived from miR-146a-5p-enriched bone marrow mesenchymal stem cells (BMSCs-miR-146a-5p-Exos) on experimental ICH. Methods: ICH was induced in adult male Sprague-Dawley rats by an intrastriatal injection of collagenase type IV. At 24 h after surgery, Exos were administrated. For detecting apoptotic cells, TUNEL staining was performed using an in situ Cell Death Detection Kit. Fluoro-Jade B staining was performed to detect degenerating neurons. Immunofluorescence assay was performed to detect the expression of myeloperoxidase (MPO) and OX-42. The binding of miR-146a-5p and its target genes was confirmed by luciferase reporter assay. Results: At 24 h after surgery, BMSCs-miR-146a-5p-Exos administration significantly improved neurological function, reduced apoptotic and degenerative neurons, and inhibited inflammatory response. Furthermore, miR-146a-5p-enriched Exos obviously inhibited the M1 polarization of microglia after ICH in rats, accompanied by the reduced expression of pro-inflammatory mediators releasing by M1 microglia including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1). Finally, we observed that miR-146a-5p directly targeted interleukin-1 receptor-associated kinase1 (IRAK1) and nuclear factor of activated T cells 5 (NFAT5), which contributed to the inflammation response and the polarization of M1 microglia/macrophages. Conclusion: We demonstrated that miR-146a-5p-riched BMSCs-Exos could offer neuroprotection and functional improvements after ICH through reducing neuronal apoptosis, and inflammation associated with the inhibition of microglial M1 polarization by downregulating the expression of IRAK1 and NFAT5.

Mechanisms of Oxidative Stress and Therapeutic Targets following Intracerebral Hemorrhage

“…Studies have determined that the level of SOD in patients with cerebral hemorrhage (113.62 ± 9.14 U/mL) is significantly lower than healthy (161.20 ± 21.12 U/mL) [ 65 ]. It is a common indicator for evaluating oxidative stress in mouse models of ICH [ 2 , 6 , 56 , 58 , 66 , 67 ].…”

Mesenchymal Stem Cells Transplantation in Intracerebral Hemorrhage: Application and Challenges

“…Recently, treatment strategies based on exosomes of MSCs have been widely reported in many diseases. The potential mechanism of exosomes treatment in the ICH mainly comprises the anti-apoptotic, neurogenesis, angiogenesis, and anti-inflammation effects through its miRNAs ( Cai et al, 2020 ; Duan et al, 2020 ).…”

Tissue Regeneration Capacity of Extracellular Vesicles Isolated From Bone Marrow-Derived and Adipose-Derived Mesenchymal Stromal/Stem Cells

“…Research in models of cutaneous wound-healing and spinal cord ischemiareperfusion injury (SCIRI) have also shown that BMMSC-EV induced macrophage M2 polarization was associated with the AK2-STAT6 signaling pathway (Sun et al, 2018), miR-223 (He et al, 2019), and miR-124-3p/Ern1 (Li et al, 2020). BMMSCderived EVs also inhibited M1 microglia activation and tissue neutrophil infiltration and reduced the expression of TNF-α, IL-1β, and IL-6 in a rat ICH model (Duan et al, 2020). Similarly, ADMSC-EV treatment in a murine model of LPS-induced lung injury mitigated injury, increased localized expression of miR-27a-3p, and induced M2 macrophage polarization via NFKB1 signaling .…”