Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stromal Cells Protect Cardiac Cells Against Hypoxia/Reoxygenation Injury by Inhibiting Endoplasmic Reticulum Stress via Activation of the PI3K/Akt Pathway

Abstract

Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of many diseases, including myocardial ischemia/reperfusion injury. We hypothesized that human umbilical cord mesenchymal stromal cells derived extracellular vesicles (HuMSC-EVs) could protect cardiac cells against hyperactive ER stress induced by hypoxia/reoxygenation (H/R) injury. The H/R model was generated using the H9c2 cultured cardiac cell line. HuMSC-EVs were extracted using a commercially available exosome isolation reagent. Levels of apoptosis-related signaling molecules and the degree of ER stress were assessed by western blot. The role of the PI3K/Akt pathway was investigated using signaling inhibitors. Lactate dehydrogenase leakage and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) analysis were used for evaluating the therapeutic effects of HuMSC-EVs in vitro. The results showed that ER stress and the rate of apoptosis were increased in the context of H/R injury. Treatment with HuMSC-EVs inhibited ER stress and increased survival in H9c2 cells exposed to H/R. Mechanistically, the PI3K/Akt pathway was activated by treatment with HuMSC-EVs after H/R. Inhibition of the PI3K/Akt pathway by a specific inhibitor, LY294002, partially reduced the protective effect of HuMSC-EVs. Our findings suggest that HuMSC-EVs could alleviate ER stress–induced apoptosis during H/R via activation of the PI3K/Akt pathway.

miR-4732-3p in Extracellular Vesicles From Mesenchymal Stromal Cells Is Cardioprotective During Myocardial Ischemia

“…EVs are involved in intracellular communication, and transfer information via a diverse cargo of cytokines, membrane-trafficking molecules, chemokines, heat shock proteins and even mRNAs and microRNAs, which trigger myriad responses in target (recipient) cells including cardiac cells ( Wu et al, 2020 ). In the setting of cardiac disease, EVs secreted by MSCs from different tissue origins have been demonstrated to mitigate ischemia/reperfusion (I/R) injury in different experimental models of AMI and I/R ( Lai et al, 2010 ; Bian et al, 2014 ; Takov et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2020 ).…”

Novel Treatment for Graft-versus-Host Disease

“…We also explored the use of MSC-derived exosomes as a substitute for MSCs to improve product consistency 63 . Exosomes contain a wide spectrum of biologically active factors, such as cytokines, growth factors, and miRNAs.…”

Circular RNA Involvement in the Protective Effect of Human Umbilical Cord Mesenchymal Stromal Cell-Derived Extracellular Vesicles Against Hypoxia/Reoxygenation Injury in Cardiac Cells

“…AC16 human cardiomyocytes were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA), cultured in DMEM added 10% FBS, 100 U/mL streptomycin, and 100 U/mL penicillin, and incubated at 37°C in an incubator filled with 5% CO 2 . ExoQuick-TC (System Biosciences, CA, USA) was used for HuMSC-EVs isolated as described previously ( 11 ).…”

“…Previous studies have shown that MSC-derived EVs can mimic the biological characteristics of MSCs, such as immune modulation and tissue damage repair ( 9 , 10 ). Our previous study also showed that human umbilical cord mesenchymal stromal cell-derived EVs (HuMSC-EVs) can protect cardiac cells against hypoxia/reoxygenation (H/R) injury via activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway ( 11 ). However, the mechanism has not been fully elucidated.…”