Human umbilical cord mesenchymal stem cells ameliorate acute graft-versus-host disease by elevating phytosphingosine

Acute graft-versus-host disease (aGVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (allo-HSCT) and even leads to death after HSCT. Human umbilical cord mesenchymal stem cells (HUCMSCs) are effective in aGVHD treatment and have mild side effects, but the underlying mechanisms remain unclear. Phytosphingosine (PHS) is known to prevent the loss of moisture from the skin; regulate epidermal cell growth, differentiation, and apoptosis; and exert bactericidal and anti-inflammatory effects. In this study, our results revealed the efficacy of HUCMSCs in alleviating aGVHD in a murine model, with striking changes in metabolism and significantly elevated PHS levels due to sphingolipid metabolism. In vitro, PHS reduced CD4⁺ T-cell proliferation, enhanced apoptosis, and reduced T helper 1 (Th1) cell differentiation. Transcriptional analysis of donor CD4⁺ T cells treated with PHS revealed significant decreases in transcripts regulating proinflammatory pathways, such as nuclear factor (NF)-κB. In vivo, the administration of PHS significantly ameliorated aGVHD development. Collectively, these beneficial effects indicate proof of concept that sphingolipid metabolites could be a safe and effective means to prevent aGVHD in the clinic.