Mesenchymal stem cell and endothelial progenitor cells coinjection improves LPS-induced lung injury via Tie2 activation and downregulation of the TLR4/MyD88 pathway.

ABSTRACT

Sepsis is one of the most important complications of infection with a high mortality rate. Recently, cell therapy has been widely used to reduce the symptoms of sepsis. It has been previously reported that mesenchymal stem cell (MSC) and endothelial progenitor cells (EPC) therapy have beneficial effects in experimental models of sepsis. The effects of coculture of MSC and EPC have not yet been used to treat sepsis. Therefore, the aim of this study was to investigate the therapeutic potential of EPC + MSC coculture on the residual effects of sepsis in a lipopolysaccharide (LPS)-induced mice model. Coinjections of EPC + MSC significantly enhanced the survival rate of LPS-induced mice, decreased concentrations of pro-inflammatory cytokines, and increased the level of anti-inflammatory cytokine. The LPS-induced mice that were treated with EPC + MSC showed a notable reduction in pulmonary edema, hepatic enzymes, and C-reactive protein level compared with the control group. Our results showed that coinjection of EPC + MSC up and downregulates Tie2 and TLR4/MyD88 signaling pathways in LPS-induced mice, respectively. Also, in vitro study showed that viability, adhesion, and migration in coculture cells is significantly decreased after being induced with 10 µg/ml LPS. Our results showed that LPS impaired the functional activity of the cocultured EPC + MSC via upregulation of the TLR4/MyD88 signaling pathway, which may be associated with decreased pTie2/Tie2 expression. In conclusion, coinjection of EPC and MSC modulated the TLR4/MyD88 signaling pathway that leads to reduce the inflammatory response. This study may provide promising results for the introduction of cocultured cells to manage infectious diseases and balance the immune response through immune regulatory function.