Let-7i-5p Mediates the Therapeutic Effects of Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells on Mitigating Endotoxin-Induced Mortality and Liver Injury in High-Fat Diet-Induced Obese Mice

Chao-Yuan Chang,Hung-Jen Shih,Yen-Hua Huang,Chun-Jen Huang,I-Tao Huang,Milton Chiang,Kung-Yen Chen

doi:10.3390/ph15010036

Abstract

Obesity complicates sepsis and increases the mortality of sepsis. We examined the effects of exosomes (from human placenta choriodecidual membrane-derived mesenchymal stem cells, pcMSCs) on preventing sepsis in obesity and the mitigating role of hsa-let-7i-5p microRNA. Obese mice (adult male C57BL/6J mice fed a high-fat diet for 12 weeks) received normal saline (HFD), endotoxin (10 mg/kg, intraperitoneal (ip); HFDLPS), endotoxin with exosomes (1 × 108 particles/mouse, ip; HLE), or endotoxin with let-7i-5p microRNA inhibitor-pretreated exosomes (1 × 108 particles/mouse, ip; HLEi). Our data demonstrated that the 48-h survival rate in the HLE (100%) group was significantly higher than in the HFDLPS (50%) and HLEi (58.3%) groups (both p < 0.05). In the surviving mice, by contrast, levels of liver injury (injury score, plasma aspartate transaminase and alanine transaminase concentrations, tissue water content, and leukocyte infiltration in liver tissues; all p < 0.05), inflammation (nuclear factor-κB activation, hypoxia-inducible factor-1α activation, macrophage activation, and concentrations of tumor necrosis factor-α, interleukin-6, and leptin in liver tissues; all p < 0.05), and oxidation (malondialdehyde in liver tissues, with p < 0.001) in the HLE group were significantly lower than in the HFDLPS group. Levels of mitochondrial injury/dysfunction and apoptosis in liver tissues in the HLE group were also significantly lower than in the HFDLPS group (all p < 0.05). Inhibition of let-7i-5p microRNA offset the effects of the exosomes, with most of the aforementioned measurements in the HLEi group being significantly higher than in the HLE group (all p < 0.05). In conclusion, exosomes mitigated endotoxin-induced mortality and liver injury in obese mice, and these effects were mediated by let-7i-5p microRNA.

Highlights

With over 650 million adults living with obesity worldwide, this condition is a global health concern [1]
The presence of exosomes was confirmed through the observation of a cup-shaped morphology, using transmission electron microscopy (TEM) (Figure 1A), a 100–150 nm morphology, using transmission electron microscopy (TEM) (Figure 1A), a 100–150 nm particle size (Figure 1B), and by positive markers for CD63 and CD9, detected using an particle size (Figure 1B), and by positive markers for CD63 and CD9, detected using an immunoblotting assay (Figure 1C)
Hsa-let-7i-5p was the most abundant miRNA identified in the exosomes (Figure 1D)

Summary

Introduction

With over 650 million adults living with obesity worldwide, this condition is a global health concern [1]. Reduced oxygenation and subsequent oxidative stress further activate hypoxia-inducible factor-1α (HIF-1α), which enhances inflammation and polarizes macrophages to the proinflammatory M1 phase [4]. Because of this damage from oxidation and inflammation, mitochondrial dysfunction is frequently observed in obesity [5]; these mechanisms work synergistically to activate apoptosis and aggravate organ dysfunction [6]. These phenomena highlight the crucial roles of oxidation, inflammation, mitochondrial dysfunction, and apoptosis in mediating multiple organ dysfunction in obesity. Effective therapies to prevent multiple organ dysfunction in patients with obesity are currently lacking [1,2]

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