Phagocytosis of Apoptotic Cells Modulates Mesenchymal Stem Cells Osteogenic Differentiation to Enhance IL-17 and RANKL Expression on CD4+T Cells

Osteogenic differentiation of mesenchymal stem cells (MSC) is important to homeostatic bone remodeling. Infiltration of mesenchymal progenitor cells to inflamed joints has been reported in collagen-induced arthritis murine model and in patients with rheumatoid arthritis (RA). Therapeutic application of MSC in RA has been suggested and under investigation. However, the underlying mechanisms on what triggers the migration of MSC from bone marrow (BM) to inflamed joints and how MSC acts in the joints remains elusive. As hemopoietic stem cells and MSC act reciprocally and excessive apoptotic cells (AC) are observed in the BM of patients with RA, we hypothesize that AC may alter MSC osteogenic differentiation resulting in bone erosion in RA. In this study, we demonstrated for the first time that MSC were able to phagocytose AC and this phagocytosis enhanced MSC osteogenic differentiation. AC-treated MSC under osteogenic differentiation expressed CXC-chemokine receptor (CXCR)-4 and CXCR5, which might enable them to migrate toward the inflamed joints. In addition, AC-treated MSC secreted interleukin (IL)-8, monocyte chemoattractant protein-1, and RANTES, which might induce chemotaxis of CD4+ T cells to the inflamed joints. Interestingly, by coculturing AC-treated MSC under osteogenic differentiation with CD4+ T cells, T helper (Th) 17 cells development was significantly enhanced and these Th17 cells promoted osteoclasts formation and bone resorption. Furthermore, the induction of Th17 cells was dependent on increased IL-6 production from major histocompatibility complex class II-expressing AC-treated MSC under osteogenic differentiation. This data provide a novel insight on the role of AC in modulating MSC osteogenic differentiation and function in inflammatory bone diseases. STEM CELLS 2010; 28: 939-954