Human placental mesenchymal stem cells regulate the antioxidant capacity of CD8+PD-1+ T cells through the CD73/ADO/Nrf2 pathway to protect against liver damage in mice with acute graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) constitutes a severe complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT), significantly reducing the survival rate of patients. Mesenchymal stem cells (MSCs) are capable of ameliorating the tissue damage caused by GVHD through exerting immunosuppressive effects; however, the relevant mechanisms require further investigation. This study used a GVHD mouse model to explore the therapeutic effects and mechanisms of human placental mesenchymal stem cells (hPMSCs) in mitigating GVHD-induced liver injury. The findings indicated that hPMSCs reduced the proportion of CD8⁺PD-1⁺ T cells in both the liver and spleen of GVHD mice, decreased reactive oxygen species (ROS) levels, and upregulated glutathione S transferase (GST) and glutathione (GSH) levels. Consistently, this led to a decrease in the expression of liver fibrosis markers, including alpha-smooth muscle actin (α-SMA) and fibronectin (FN). Moreover, CD8⁺PD-1⁺ T cells and ROS were positively correlated with α-SMA and FN, respectively, whereas GST and GSH were negatively correlated with them. hPMSCs with low expression in CD73 attenuated this effect. In vitro studies demonstrated that hPMSCs upregulated the expression of nuclear factor-E2-related factor 2 (Nrf2) via the CD73/adenosine (ADO) pathway, regulated oxidative metabolism, and reduced the number of CD8⁺PD-1⁺ T cells. The results suggested that hPMSCs contributed to the regulation of redox homeostasis and reduced the proportion of CD8⁺PD-1⁺ T cells through the CD73/ADO/Nrf2 signaling pathway, thereby alleviating liver injury associated with GVHD.