Sphingosine-1-phosphate mediates the therapeutic effects of bone marrow mesenchymal stem cell-derived microvesicles on articular cartilage defect

Microvesicles (MVs) are emerging as a new mechanism of intercellular communication by transferring cellular components to target cells, yet their function in disease is just being explored. However, the therapeutic effects of MVs in cartilage injury and degeneration remain unknown. We found MVs contained high levels of sphingosine-1-phosphate (S1P) compared with the original bone marrow mesenchymal stem cells (MSCs). The enrichment of S1P in MVs was mediated by sphingosine kinase I (SphK1), but not by sphingosine kinase 2 (SphK2). Co-culture of human chondrocytes with MVs resulted in increased proliferation of chondrocytes in vitro, which was mediated by activation of S1P receptor 1 (S1PR(1)) expressed on chondrocytes. Meanwhile, MVs inhibited interleukin 1 beta-induced human chondrocytes apoptosis in a dose dependent manner. Furthermore, uptake of MVs by primary cultures of human chondrocytes was mediated by CD44 expressed by MVs. Anti-CD44 antibody significantly reduced the uptake of fluorescent protein-labeled MVs by chondrocytes. Further, blocking S1P by its neutralizing antibody significantly inhibited the therapeutic effects of MVs in vivo. Taken together, MVs showed therapeutic potential for treatment of clinical cartilage injury. This therapeutic potential is due to CD44-mediated uptake of MVs by chondrocytes and the S1P/S1PR(1) axis-mediated proliferative effects of MVs on chondrocytes.