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 [ABSTRACT FROM AUTHOR]