Exosomes from Endothelial Progenitor Cells Improve the Outcome of a Murine Model of Sepsis

Abstract

Microvascular dysfunction leads to multi-organ failure and mortality in sepsis. Our previous studies demonstrated that administration of exogenous endothelial progenitor cells (EPCs) confers protection in sepsis as evidenced by reduced vascular leakage, improved organ function, and increased survival. We hypothesize that EPCs protect the microvasculature through the exosomes-mediated transfer of microRNAs (miRNAs). Mice were rendered septic by cecal ligation and puncture (CLP), and EPC exosomes were administered intravenously at 4 hr after CLP. EPC exosomes treatment improved survival, suppressing lung and renal vascular leakage, and reducing liver and kidney dysfunction in septic mice. EPC exosomes attenuated sepsis-induced increases in plasma levels of cytokines and chemokine. Moreover, we determined miRNA contents of EPC exosomes with next-generation sequencing and found abundant miR-126-3p and 5p. We demonstrated that exosomal miR-126-5p and 3p suppressed LPS-induced high mobility group box 1 (HMGB1) and vascular cell adhesion molecule 1 (VCAM1) levels, respectively, in human microvascular endothelial cells (HMVECs). Inhibition of microRNA-126-5p and 3p through transfection with microRNA-126-5p and 3p inhibitors abrogated the beneficial effect of EPC exosomes. The inhibition of exosomal microRNA-126 failed to block LPS-induced increase in HMGB1 and VCAM1 protein levels in HMVECs and negated the protective effect of exosomes on sepsis survival. Thus, EPC exosomes prevent microvascular dysfunction and improve sepsis outcomes potentially through the delivery of miR-126.

YBX-1 mediated sorting of miR-133 into hypoxia/reoxygenation-induced EPC-derived exosomes to increase fibroblast angiogenesis and MEndoT

“…Furthermore, exosomes had been shown to carry different nucleic acids, including microRNAs (miRNAs), which are acquired by recipient cells to regulate their own fate [10,11]. Previous studies found that miRNAs in exosomes from endothelial progenitor cells improved outcomes of patients with cardiovascular disease [12] and lipopolysaccharide-induced acute lung injury [13] and also of a murine model of sepsis [12].…”

Exosomes in Sepsis Diagnosis and Treatment

“…Zhou found in the experiment that exosomes miR-126-5p and 3p can inhibit LPS-induced human microvascular endothelial cells (HMVECs) high mobility group protein b1 (HMGB1) and vascular cell adhesion molecule 1 (VCAM1) levels, It was confirmed that the use of EPR exosomes to deliver miR-126 can prevent microvascular dysfunction, attenuate the increase in plasma cytokine and chemokine levels induced by sepsis, inhibit lung and renal vascular leakage in vital organs, and improve the survival rate of mice with sepsis [27]. In the mouse kidney ischemia/reperfusion injury model, the level of urinary extracellular ATF3 (activating transcription factor 3) was detected to be higher than normal before serum creatinine concentration had increased [28].…”

Recent progress in microRNA-based delivery systems for the treatment of human disease

“…As they can circumvent endocytosis and escape from phagocytosis by the RES, exosomes have high delivery efficacy. In a recent study, endothelial progenitor cell-derived exosomes containing abundant miRNA-126-3p and 5p could attenuate organ injury and vascular permeability in cecal ligation and puncture (CLP)-induced sepsis [103]. In another study, Wen et al utilized human bone marrow mesenchymal stem cells (hBMSCs) and their exosomes (which are rich in siFas and anti-miRNA-375) to restrain islet apoptosis and primary nonfunction (PNF) during islet transplantation in humanized NOD scid gamma (NSG) mice [104].…”