Exosomes derived from microRNA-30b-3p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting SAA3

Exp Cell Res. 2019 Oct 15;383(2):111454. doi: 10.1016/j.yexcr.2019.05.035. Epub 2019 Jun 4.

Abstract

Mesenchymal stem cells (MSCs) have been widely documented for their potential role in the treatment of various clinical disorders, including acute lung injury (ALI). ALI represents a clinical syndrome associated with histopathological diffuse alveolar damage. Recent evidence has demonstrated that exosomes derived from MSCs may serve as a reservoir of anti-apoptotic microRNAs (miRs) conferring protection from certain diseases. Hence, the current study was performed with the aim of investigating whether MSCs-exosomal miR-30b-3p could confer protection against ALI. A bioinformatic analysis and a dual luciferase assay were initially performed to verify that SAA3 was highly-expressed in ALI which was confirmed to be a target gene of miR-30b-3p. Next, the lipopolysaccharide (LPS)-treated type II alveolar epithelial cells (AECs) (MLE-12) were transfected with mimics or inhibitors of miR-30b-3p, or sh-SAA3. It was revealed that LPS induced AEC apoptosis, which could be inhibited by overexpressing miR-30b-3p by down-regulating the expression of SAA3. After co-culture of PKH26-labeled exosomes with MLE-12 cells, we found that the number of PKH26-labeled exosomes endocytosed by MLE-12 cells gradually increased. Furthermore, the LPS-treated MLE-12 cells co-cultured with MSC-exosomes overexpressing miR-30b-3p exhibited increased miR-30b-3p, decreased SAA3 level, as well as increased cell proliferation, accompanied by diminished cell apoptosis in LPS-treated MLE-12 cells. Finally, the protective effect of MSCs-exosomal miR-30b-3p on the AECs in vivo was investigated in an ALI mouse model with tail vein injection of MSC-exosomes with elevated miR-30b-3p, showing that overexpression of miR-30b-3p in MSC-exosomes conferred protective effects against ALI. Taken together, these findings highlighted the potential of MSC-exosomes overexpressing miR-30b-3p in preventing ALI. The exosomes derived from MSCs hold potential as future therapeutic strategies in the treatment of ALI.

Keywords: Acute lung injury; Alveolar epithelial cells; Exosome; Mesenchymal stem cells; Serum amyloid A3; microRNA-30b-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced*
  • Acute Lung Injury / genetics
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / prevention & control*
  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Exosomes / genetics
  • Exosomes / metabolism
  • Exosomes / physiology*
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides*
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Protective Agents / metabolism
  • Serum Amyloid A Protein / genetics*
  • Serum Amyloid A Protein / metabolism

Substances

  • Lipopolysaccharides
  • MicroRNAs
  • Mirn30d microRNA, mouse
  • Protective Agents
  • Saa3 protein, mouse
  • Serum Amyloid A Protein