Exosomal sphingosine 1-phosphate secreted by mesenchymal stem cells regulated Treg/Th17 balance in aplastic anemia

This study was designed to explore whether exosomal sphingosine 1-phosphate (S1P) from mesenchymal stem cells (MSCs) regulate the Treg/Th17 balance in aplastic anemia (AA) patients and to validate the underlying mechanism. To address this, exosomes from human bone marrow MSCs (MSCs-Exos) were co-cultured with CD4⁺ T cells from AA patients (AA CD4⁺ T cells), which were transfected with si-S1PR1, si-S1PR3, or not. The proportion of Th17 and Treg was evaluated by flow cytometry. The levels of Th17-associated interleukin-17 (IL-17), Treg-associated IL-10, and transforming growth factor-β were determined by ELISA. S1P content in MSCs-Exos isolated from control, si-SphK1, or si-SphK2 transfected MSCs was examined by LC-MS/MS. Hematoxylin and eosin staining of bone marrow tissues was performed to evaluate the effect of MSCs-Exos in AA mice. Our results showed that MSCs-Exos reversed the increased Th17/Treg in AA through SphK1-mediated exosomal S1P enrichment. Furthermore, the promotion of Treg differentiation by exosomal S1P from MSCs was mediated through the receptor S1PR1 expressed on CD4⁺ T cells. Further in vivo experiments showed that MSCs-Exos reversed the increased Th17/Treg and alleviated AA progression in AA mice. In summary, SphK1-mediated enrichment of exosomal S1P secreted by MSCs reversed the increased Treg/Th17 ratio via the receptor S1PR1 in AA patients. © 2019 IUBMB Life, 71(9):1284-1292, 2019.