Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p

Mingyang Shao,Zhenru Wu,Xiaoyue Cao,Qing Xu,Yongjie Zhou,Yujun Shi,Menglin Chen,Yuwei Chen,Yuke Shu,Rong Yao,Hong Bu,Bo Zhang

doi:10.1186/s13287-020-1550-0

Abstract

BackgroundUsing a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys. MSCs are considered to play a therapeutic role under different stresses by adaptively producing specific factors, prompting us to investigate the factors that hUC-MSCs produce in response to high serum levels of IL-6, which plays a critical role in initiating and accelerating ALF.MethodsWe stimulated hUC-MSCs with IL-6, and the hUC-MSC-derived exosomes were deeply sequenced. The miRNAs in the exosomes that have potential to suppress IL-6-associated signaling pathway were screened, and the role of one of the most possible miRNAs was tested in the mouse model of inflammatory liver injury.ResultWe determined that miR-455-3p, which is secreted through exosomes and potentially targets PI3K signaling, was highly produced by hUC-MSCs with IL-6 stimulation. The miR-455-3p-enriched exosomes could inhibit the activation and cytokine production of macrophages challenged with lipopolysaccharide (LPS) both in vivo and in vitro. In a chemical liver injury mouse model, enforced expression of miR-455-3p could attenuate macrophage infiltration and local liver damage and reduce the serum levels of inflammatory factors, thereby improving liver histology and systemic disorder.ConclusionsmiR-455-3p-enriched exosomes derived from hUC-MSCs are a promising therapy for acute inflammatory liver injury.

Highlights

Using a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys
Conclusions: miR-455-3p-enriched exosomes derived from hUC-Mesenchymal stem cells (MSCs) are a promising therapy for acute inflammatory liver injury
Results hUC-MSC-derived exosomes inhibit macrophage activation We first tested whether hUC-MSCs can secrete exosomes under IL-6 stimulation. hUC-MSCs at passage 3 were cultured with 1 ng/mL IL-6 for 48 h

Summary

Introduction

Using a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys. Shao et al Stem Cell Research & Therapy (2020) 11:37 monkey and mouse toxic liver injury models, suppression of monocyte activation, especially inhibition of IL-6 secretion, can effectively control the occurrence of a cytokine storm, ameliorate liver damage, and improve animal survival. MSCs have been used in mouse models for the treatment of a variety of diseases, including acute lung injury, myocardial infarction, diabetes, sepsis, liver dysfunction, and acute renal failure [4, 5]. MSC-based therapies have been strongly limited by their unclear mechanism of action [5, 9]

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Conclusion