Abstract
Previous studies have reported that the long non-coding RNA SNHG12 (lncRNA SNHG12) plays a critical role in regulating the function of mesenchymal stem cells (MSCs); however, the effect of lncRNA SNHG12 on MSCs in injured brain tissue has rarely been reported. We studied the effect and mechanism of lncRNA SNHG12-modified mesenchymal stem cells (MSCs) in treating brain injuries caused by ischemia/reperfusion (I/R). I/R treated rat brain microvascular endothelial cells (BMECs) were co-cultured with MSCs or I/R pretreated MSCs. Next, BMEC proliferation was detected by using CCK-8 and EdU assays, and cell apoptosis was determined by using flow cytometry and the Hoechst staining method. Autophagy of BMECs was determined using immunofluorescence and expression of associated pathway proteins were measured by western blotting. Moreover, BMEC proliferation, apoptosis, and autophagy were also determined after the BMECs had been co-cultured with shSNHG12-MSCs. In addition, a rat model of middle cerebral artery occlusion (MCAO) was used to further confirm the findings obtained with cells. I/R treatment significantly decreased the proliferation of BMECs, but increased their levels of SNHG12 expression, apoptosis, and autophagy. However, co-culturing of BMECs with MSCs markedly alleviated the reduction in BMEC proliferation and the increases in BMEC apoptosis and autophagy, as well as the phosphorylation of PI3K, AKT, and mTOR proteins in BMECs that had been induced by I/R. Furthermore, shSNHG12 remarkably enhanced the effects of MSCs. In addition, an injection MSCs reduced the infarct areas and rates of cell apoptosis in MACO rats, and reduced the phosphorylation of PI3K, AKT, and mTOR proteins. Moreover, shSNHG12 enhanced the ameliorative effect of MSCs in treating brain injuries in the MACO rats. In conclusion, silencing of SNHG12 enhanced the effects of MSCs in reducing apoptosis and autophagy of BMECs by activating the PI3K/AKT/mTOR signaling pathway.
Highlights
Ischemic stroke, which is caused by an interruption of blood supply, is a leading cause of mortality and morbidity worldwide (Farrell-Dillon et al, 2017)
The results showed that silencing Small nucleolar RNA host gene 12 (SNHG12) could significantly promote the apoptosis, but inhibit the proliferation ability of brain microvascular endothelial cells (BMECs) after I/R treatment (Supplementary Figures S1B,C), indicating that SNHG12 might play critical role in responding to I/R injury
The results showed that I/R treatment significantly decreased the proliferation of BMECs, while co-culture with mesenchymal stem cells (MSCs) markedly alleviated that reduction
Summary
Ischemic stroke, which is caused by an interruption of blood supply, is a leading cause of mortality and morbidity worldwide (Farrell-Dillon et al, 2017). Cerebral tissue damage that occurs after ischemia significantly threatens the survival and quality of life of stroke patients (Liu et al, 2015; Siket, 2016). Multiple mechanisms, such as inflammation, apoptosis, oxidative damage, and excitatory neurotransmitter disorder, are involved in cerebral ischemia/reperfusion (I/R) injuries (Rodrigo et al, 2013; Chen et al, 2014; Sharma et al, 2018). Numerous treatment agents, including UPE1-400 (Connell et al, 2016), Pannexin-1 (Sharma et al, 2018), and Ginsenoside-Rg1 (Xie et al, 2015), have been evaluated for their ability to reduce the severity of I/R injuries and improve stroke outcomes in animal models. The exact outcomes produced by these agents remain unclear, and require further confirmation in the clinic
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