Human placental mesenchymal stromal cells alleviate intestinal oxidative damage in mice with graft-versus-host disease via CD73/adenosine/PI3K/Akt/GSK-3β axis

Abstract

Background: Intestinal damage is a common and serious complication in patients with graft-versus-host disease (GVHD). Human placental mesenchymal stromal cells (hPMSCs) ameliorate GVHD tissue damage by exerting anti-oxidative effects; however, the underlying mechanisms remain not fully clear.

Methods: A GVHD mouse model and tumor necrosis factor-α (TNF-α)-stimulated human colon epithelial cell lines NCM460 and HT-29 cells were used to investigate the mechanisms of hPMSCs alleviating GVHD-induced intestinal oxidative damage.

Results: hPMSCs reduced TNF-α concentrations and the number of CD3⁺TNF-α⁺ T-cells, which were negatively correlated with the expression of claudin-1, occludin, and ZO-1, through CD73 in the colon tissue of GVHD mice. Meanwhile, hPMSCs reduced the mean fluorescence intensity (MFI) of reactive oxygen species (ROS) and the concentration of malondialdehyde (MDA), promoted superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, as well as claudin-1, occludin, and ZO-1 expression, in colonic epithelial cells of GVHD mice and TNF-α-stimulated cells via CD73. Moreover, hPMSCs upregulated adenosine (ADO) concentrations in GVHD mice and TNF-α-stimulated cells and mitigated the loss of tight junction proteins via the CD73/ADO/ADO receptors. Further analysis showed that hPMSCs diminished Fyn expression and enhanced Nrf2, GCLC, and HO-1 expression in both TNF-α-stimulated cells and colonic epithelial cells of GVHD mice by activating PI3K/Akt/GSK-3β pathway.

Conclusions: The results suggested that hPMSC-mediated redox metabolism balance and promoted tight junction protein expression were achieved via CD73/ADO/PI3K/Akt/GSK-3β/Fyn/Nrf2 axis, by which alleviating intestinal oxidative injury in GVHD mice.

Keywords: CD73; Graft-versus-host disease; Human placental mesenchymal stromal cell; Nrf2; Reactive oxygen species.