Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way

Abstract

Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (ExoH) are superior to those from normoxia-treated MSCs (ExoN) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. ExoH resulted in significantly higher survival, smaller scar size and better cardiac functions recovery. ExoH conferred increased vascular density, lower cardiomyocytes (CMs) apoptosis, reduced fibrosis and increased recruitment of cardiac progenitor cells in the infarcted heart relative to ExoN. MicroRNA analysis revealed significantly higher levels of microRNA-210 (miR-210) in ExoH compared with ExoN. Transfection of a miR-210 mimic into endothelial cells (ECs) and CMs conferred similar biological effects as ExoH. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secretion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the beneficial effects of ExoH. In conclusion, hypoxic culture augments miR-210 and nSMase2 activities in MSCs and their secreted exosomes, and this is responsible at least in part for the enhanced cardioprotective actions of exosomes derived from hypoxia-treated cells.

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Increasing evidence has indicated that the EV microRNA (miRNA) content as one of their most likely paracrine mechanism(s) of action. Several miRNAs have been associated with MSC-EV cardioprotective, pro-survival and angiogenic effects, including, for example, miR-21 [187]; miR-125b [188]; miR-320d [189]; miR-95-3p [190]; miR-210 [191]; miR-29 and miR-24 [180]. Additionally, EVs have been shown to biochemically restore ATP and NADH levels and redox state within the injured tissue [192].…”

Human umbilical cord mesenchymal stem cells derived exosomes exert antiapoptosis effect via activating PI3K/Akt/mTOR pathway on H9C2 cells

“…Other studies also found significant enrichment of miRNA-125b-5p and miRNA-210 in exosomes from hypoxia-treated MSCs compared with those from normoxic MSCs. 30,31 In addition, Han et al 32 demonstrated that the levels of many cytokines, included vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor were significantly higher in the exosomes derived from hypoxia-preconditioned adipose MSCs than in the exosomes derived from normoxic adipose MSCs. Many of these miRNAs and cytokines participate in the regulation of apoptosis.…”

Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

“…Wang et al demonstrated that miR-210 enriched in BMSC-EVs drives endothelial proliferation and migration in vitro, and it improves cardiac angiogenesis and cardiac function after MI in mice by targeting Ephrin-A3 [17]. Zhu et al showed that BMSC hypoxic pretreatment increased the enrichment of angiogenesis-associated miRNAs in BMSC-EXs, which promoted angiogenesis more effectively and improved the therapeutic effects of MI treatment in mice [18].…”

“…revealed that EXs produced from hypoxia-preconditioned mouse BMSCs exhibited considerably improved learning and memory capabilities and reduced plaque deposition, neuroinflammation, and Aβ expression in an AD mouse model [11]. Zhu et al showed that hypoxia (0.5% O 2 ) stimulated exosomal mRNA-210 secretion through nSMase2 in mouse BMSCs to promote angiogenesis and improve cardiac function in a mouse model of MI [18].…”

“…Wang et al demonstrated that miR-210 enriched in BMSC-EVs drives endothelial proliferation and migration in vitro, and it improves cardiac angiogenesis and cardiac function after MI in mice by targeting Ephrin-A3 [17]. Zhu et al showed that BMSC hypoxic pretreatment increased the enrichment of angiogenesis-associated miRNAs in BMSC-EXs, which promoted angiogenesis more effectively and improved the therapeutic effects of MI treatment in mice [18].Preclinical studies have indicated that BMSC-EXs could alleviate inflammatory responses in cardiovascular diseases. Macrophages and neutrophils are activated and recruited to the injured site after a MI and they release a large number of inflammatory factors that trigger a series of inflammatory reactions.…”