Exosomes of Human Umbilical Cord MSCs Protect Against Hypoxia/Reoxygenation-Induced Pyroptosis of Cardiomyocytes via the miRNA-100-5p/FOXO3/NLRP3 Pathway

Abstract

BackgroundAcute myocardial infarction (AMI) is one of the leading causes of morbidity and death worldwide. Studies have indicated that microRNAs in mesenchymal stem cell (MSC)-derived exosomes are crucial for treating various diseases.MethodsHuman umbilical cord MSC (hucMSC)-derived exosomes (hucMSC-exo) were isolated and used to treat cardiomyocytes that underwent hypoxia/reoxygenation (H/R) injury. Bioluminescence assessment was used to study binding of miRNA to its targeting gene.ResultsWe found that H/R decreased the viability of AC16 cells, increased the expression of NLRP3, and activated caspase-1(p20) and GSDMD-N as well as release of IL-1β and IL-18, and such effects were abolished by administration of hucMSC-exo. Administration of exosomes from negative scramble miRNA (NC)-transfected hucMSCs blocked H/R-caused lactate dehydrogenase release, pyroptosis, and over-regulation of NLRP3 and activated caspase-1(p20) and GSDMD-N as well as release of IL-1β and IL-18. More importantly, in comparison to exsomes from NC-transfected hucMSCs, exsomes from miR-100-5p-overexpressing hucMSCs had more obvious effects, and those from miR-100-5p-inhibitor-transfected hucMSCs showed fewer effects. Functional study showed that miR-100-5p bound to the 3’-untranslated region (3’-UTR) of FOXO3 to suppress its transcription. Moreover, overexpression of FOXO3 abolished the protective effects of miR-100-5p.ConclusionEnriched miR-100-5p in hucMSC-exo suppressed FOXO3 expression to inhibit NLRP3 inflammasome activation and suppress cytokine release and, therefore, protected cardiomyocytes from H/R-induced pyroptosis and injury.

hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis

“…Another study found that MSC-derived exosomal miR-410 was a crucial regulator of pyroptosis by directly binding to NLRP3 mRNA to suppress the NLRP3 pathway [ 55 ]. Similarly, MSC-derived exosomes effectively reduced NLRP3 inflammasome to ameliorate intervertebral disc degeneration [ 56 ] and protected against hypoxia/reoxygenation-induced pyroptosis of cardiomyocytes through the miRNA-100-5P/FOXO3/NLRP3 pathway [ 57 ]. Our study is consistent with these findings in that hucMSC-derived exosomes decrease the activation of NLRP3 inflammasomes in macrophages and delay the progress of cell pyroptosis in vitro.…”

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Oxygen-Glucose Deprivation/Reperfusion-Induced Microglial Pyroptosis by Promoting FOXO3a-Dependent Mitophagy

“…The above findings suggest that the reduction in microglial pyroptosis may be the key for curing neonatal HIBD. Recently, MSC-exos were reported to inhibit pyroptosis in a variety of cells [ 17 – 19 ]. However, whether MSC-exos improve neonatal HIBD by inhibiting microglial pyroptosis remains unknown.…”

Regulation of pyroptosis in cardiovascular pathologies: Role of noncoding RNAs

“…99 Enriched miR-100-5p in human umbilical cord mesenchymal stem cells (MSCs)-derived exosomes protects against H/Rinduced cardiomyocyte pyroptosis and injury through suppressing FOXO3 expression, which inhibits the activation of NLRP3 inflammasome and the release of LDH/cytokines. 100 Exosomal miR-320b derived from MSCs directly targets NLPR3 protein to inhibit pyroptosis and protect myocardium against I/R injury. 101 However, under HR treatment, exosomal miR-29a derived from M1 macrophages promotes cardiomyocyte pyroptosis by targeting Mcl-1.…”