Abstract
Hypoxia-ischemia brain damage (HIBD) is a neurological disorder occring in neonates, which is exacerbated by neuronal apoptosis. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as a promising strategy for treating or preventing ischemia-related diseases. However, their mechanisms in HIBD remain unclear. Thus, we aimed to address the role of EV-derived microRNA (miR)-410 in HIBD. Neonatal HIBD mouse model was constructed using HI insult, from which neurons were isolated, followed by exposure to oxygen glucose deprivation (OGD). EVs were isolated from human umbilical cord (hUC)-derived MSCs. In silico analyses, dual-luciferase reporter gene and chromatin immunoprecipitation assays were adopted to determine relationships among miR-410, histone deacetylase 1 (HDAC1), early growth response protein 2 (EGR2), and B cell lymphoma/leukemia 2 (Bcl2). The functional roles of EV-derived miR-410 were determined using loss- and gain-of functions experiments, and by evaluating neuronal viability, cell-cycle distribution and neuronal apoptosis in vitro as well as modified neurological severity score (mNSS), edema formation, and cerebral infarction volume in vivo. hUC-MSCs-derived EVs protected against HIBD in vivo and inhibited the OGD-induced neuronal apoptosis in vitro. miR-410 was successfully delivered to neurons by hUC-MSCs-EVs and negatively targeted HDAC1, which inversely mediated the expression of EGR2/Bcl2. Upregulation of EV-derived miR-410 promoted the viability but inhibited apoptosis of neurons, which was reversed by HDAC1 overexpression. EV-derived miR-410 elevation reduced mNSS, edema formation, and cerebral infarction volume by increasing EGR2/Bcl2 expression through downregulating HDAC1 expression in vivo. In summary, EV-derived miR-410 impeded neuronal apoptosis by elevating the expression of EGR2/Bcl2 via HDAC1 downregulation, thereby providing a potential strategy for treating or preventing HIBD.
Highlights
Perinatal hypoxia-ischemia (HI) is the main cause of acute neonatal brain injury, leading to long-term neurological impairments including behavioral, social, cognitive, and even functional motor deficits (Li et al, 2017)
Immunoblotting results (Figure 1C) identified that extracellular vesicles (EVs) were positive for CD63 molecule (CD63), ALIX, and TSG101, and negative for GM130, suggesting the successful isolation of EVs from human umbilical cord (hUC)-Mesenchymal stem cells (MSCs)
Immunofluorescence results (Figure 1D) revealed red-labeled (PKH26) EVs in hippocampus, indicating the uptake of EVs by hippocampus in mice. modified neurological severity score (mNSS) (Figure 1E) was analyzed and results displayed that mNSS substantially increased in Hypoxia-ischemia brain damage (HIBD) mice compared with shamoperated mice, while MSCs-EVs treatment markedly reduced the mNSS in comparison to phosphate buffer saline (PBS) treatment in HIBD mice (p < 0.05)
Summary
Perinatal hypoxia-ischemia (HI) is the main cause of acute neonatal brain injury, leading to long-term neurological impairments including behavioral, social, cognitive, and even functional motor deficits (Li et al, 2017). A previous study has noted that enhanced neuronal cell death correlates to exacerbated HI in the immature brain (Rodriguez et al, 2018). Mesenchymal stem cells (MSCs) confer protection against hypoxia-ischemia brain damage (HIBD) (Zheng et al, 2018). Extracellular vesicles (EVs) released from human umbilical cordderived MSCs (hUC-MSCs) exert neuroprotective functions against perinatal brain injury and reduce neuronal cell death (Thomi et al, 2019a). Elucidating the inhibitory mechanisms of MSCs-derived EVs on neuronal apoptosis is critical to attenuating HIBD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
