BackgroundMesenchymal stromal cell (MSC)–based therapy has great potential to modulate chronic inflammation and enhance tissue regeneration. Crosstalk between MSC-lineage cells and polarized macrophages is critical for bone formation and remodeling in inflammatory bone diseases. However, the translational application of this interaction is limited by the short-term viability of MSCs after cell transplantation.MethodsThree types of genetically modified (GM) MSCs were created: ( 1) luciferase-expressing reporter MSCs; ( 2) MSCs that secrete interleukin (IL)-4 either constitutively; and ( 3) MSCs that secrete IL-4 as a response to nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) activation. Cells were injected into the murine distal femoral bone marrow cavity. MSC viability and bone formation were examined in vivo. Cytokine secretion was determined in a femoral explant organ culture model. ResultsThe reporter MSCs survived up to 4 weeks post-implantation. No difference in the number of viable cells was found between high (2.5?×?106) and low (0.5?×?106) cell-injected groups. Injection of 2.5?×?106 reporter MSCs increased local bone mineral density at 4 weeks post-implantation. Injection of 0.5?×?106 constitutive IL-4 or NFκB-sensing IL-4–secreting MSCs increased bone mineral density at 2 weeks post-implantation. In the femoral explant organ culture model, LPS treatment induced IL-4 secretion in the NFκB-sensing IL-4–secreting MSC group and IL-10 secretion in all the femur samples. No significant differences in tumor necrosis factor (TNF)α and IL-1β secretion were observed between the MSC-transplanted and control groups in the explant culture.DiscussionTransplanted GM MSCs demonstrated prolonged cell viability when transplanted to a compatible niche within the bone marrow cavity. GM IL-4–secreting MSCs may have great potential to enhance bone regeneration in disorders associated with chronic inflammation. |
