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

  • Stem Cell Res Ther. 2020 Jan 23;11(1):37. doi: 10.1186/s13287-020-1550-0.
Mingyang Shao  1 ,  Qing Xu  1 ,  Zhenru Wu  1 ,  Yuwei Chen  1 ,  Yuke Shu  1 ,  Xiaoyue Cao  1 ,  Menglin Chen  1 ,  Bo Zhang  2 ,  Yongjie Zhou  1 ,  Rong Yao  3 ,  Yujun Shi  4  5 ,  Hong Bu  1  6
Affiliations
  • 1. Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China.
  • 2. Sichuan Stem Cell Bank & Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, 610037, China.
  • 3. The Emergency Department, West China Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
  • 4. Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, China. [email protected].
  • 5. Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
  • 6. Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.
PMID: 31973730 DOI: 10.1186/s13287-020-1550-0
Abstract

Background: 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. 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.

Methods: We 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.

Result: We 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.

Conclusions: miR-455-3p-enriched exosomes derived from hUC-MSCs are a promising therapy for acute inflammatory liver injury.

Keywords
Acute liver injury; Exosome; Inflammation; hUC-MSCs; microRNA-455-3p.
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