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Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into various cell types and secrete extracellular vesicles (EVs) that transport bioactive molecules and mediate intercellular communication. MSCs and MSC-derived EVs (MSC-EVs) have shown promising therapeutic effects in several diseases. However, their procoagulant activity and thrombogenic risk may limit their clinical safety. In this review, we summarize current knowledge on procoagulant molecules expressed on the surface of MSCs and MSC-EVs, such as tissue factor and phosphatidylserine. Moreover, we discuss how these molecules interact with the coagulation system and contribute to thrombus formation through different mechanisms. Additionally, various confounding factors, such as cell dose, tissue source, passage number, and culture conditions of MSCs and subpopulations of MSC-EVs, affect the expression of procoagulant molecules and procoagulant activity of MSCs and MSC-EVs. Therefore, herein, we summarize several strategies to reduce the surface procoagulant activity of MSCs and MSC-EVs, thereby aiming to improve their safety profile for clinical use. [ABSTRACT FROM AUTHOR]

Enhancement of Connexin43 (Cx43) and ferroptosis are respectively associated with the exacerbation of myocardial ischemia-reperfusion injury (MIRI) in diabetes. Myocardial vulnerability to ischemic insult has been shown to vary during early and later phases of diabetes in experimental settings. Whether or not Connexin43 (Cx43) and ferroptosis interplay during MIRI in diabetes is unknown. We, thus, aimed to investigate whether or not the content of myocardial Cx43 may be attributable to myocardial vulnerability to MIRI at different stages of diabetes and also to explore the potential interplay between Cx43 and ferroptosis in this pathology. Age-matched control and subgroups of Streptozotocin-induced diabetic mice were subjected to MIRI induced by 30 minutes coronary artery occlusion and 2 hours reperfusion respectively at 1, 2 and 5 weeks of diabetes. Rat cardiac H9C2 cells were exposed to high glucose (HG) for 48h in the absence or presence of Cx43 gene knockdown followed by hypoxia/reoxygenation (HR) respectively for 6 and 12 hours. Post-ischemic myocardial infarct size was reduced in 1 and 2 weeks DM mice concomitant with enhanced GPX4 and reduced cardiac Cx43 and ferroptosis as compared to control. By contrast, cardiac GPX4 was significantly reduced while Cx43 increased at DM 5 weeks (D5w) which was correspondent to significant increases in ferroptosis and myocardial infarction. Post-ischemic cardiac function was improved in 1 and 2 weeks but worsened in 5w DM mice as compared with non-diabetic control. GAP19 (Cx43 inhibitor) significantly attenuated ferroptosis and reduced myocardial infarction in D5w mice. Erastin (ferroptosis activator) reversed the cardioprotective effect of GAP19. In vitro, HR significantly reduced cell viability accompanied with reduced GPX4 but elevated Cx43 expression, MDA production and ferroptosis. Cx43 gene knockdown in H9C2 resulted in a significant increase in GPX4, reduction in MDA and ferroptosis, and subsequently reduced post-hypoxic cell viability. The beneficial effects of Cx43 gene knock-down was minified or eliminated by Erastin. It is concluded that Cx43 overexpression exacerbates MIRI under diabetic conditions via promoting ferroptosis, while its down-regulation at early state of diabetes is attributable to enhanced myocardial tolerance to MIRI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)