TARGETING IFN-γ+ T CELLS VIA SUPERANTIGEN SEC2 TO PRIME PERIOSTEAL STEM CELLS FOR ENHANCED OSTEOPOROTIC FRACTURE HEALING

The last decade has witnessed increasing evidence which highlights the role of T cells in bone regeneration. Various T cell subsets are involved in fracture healing by orchestrating a series of events that modulate bone formation and remodeling. Staphylococcal enterotoxins (SEs) are a family of heat-stable enterotoxins which can elicit a variety of biological activities by activating T cells. Our previous study showed that systemic administration of low-dose staphylococcal enterotoxin C2 (SEC2) dramatically promoted bone formation in ovariectomy (OVX) mice via IFN-γ signaling. However, the effects of local sustained release of SEC2 by bioactive materials on osteoporotic fracture healing remain unclear. In this study, we prepared SEC2-laden PLGA microspheres which achieved a stable and sustained release of SEC2 within 2 weeks. We found the local injection of SEC2-laden PLGA microspheres at the fracture site in osteoporotic mice during the inflammatory stage significantly improved the mechanical properties of the healed femur at week 6 post fracture, and this promoting effect was dramatically diminished in T cell-deficient mice. Mechanistic studies further revealed that lymphocytes stimulated with the SEC2-laden PLGA microspheres exhibited significant activation of T cells, along with enhanced expression levels of IFN-γ and IL-2. Besides, periosteal stem cells which co-cultured with SEC2-stimulated T cells exhibited enhanced capacities of migration, stronger immunomodulatory abilities, and improved osteogenic differentiation potential, and these beneficial effects were relatively diminished when IFN-γ signaling was blocked using cells from Ifngr1 knockout mice. In summary, this study explored the therapeutic potential of SEC2-laden PLGA microspheres on osteoporotic fracture healing and determined that IFN-γ+ T cells can prime periosteal stem cells and promote osteogenesis, suggesting that targeting T cell immunity may serve as an alternative strategy for augmenting bone regeneration.