Effects of immune cells on mesenchymal stem cells during fracture healing

Figure 6 Schematic overview of the regulatory role of T-cells during fracture healing. Fracture healing is affected by interactions between mesenchymal stem cells (MSCs) and T-cells. However, the effect strongly depends on the activation or differentiation status of the T-cells, which is in CD4⁺ T-cells strongly dependent on activation of signal transducer and activator of transcription (STAT) signaling. Th1 cells are primed by interferon gamma (IFN-γ) and interleukin 12 (IL-12), which activate STAT-1 and STAT4 signaling in these cells. Th1 cells then secrete factors e.g., tumor necrosis factor alpha (TNF-α), IFN-γ, or IL-2. Th17 cells are primed by transforming growth factor beta (TGF-β), IL-1β and IL-6, which activate STAT3 signaling in the cells. Th17 cells then secrete factors e.g., IL-17 and receptor activator of nuclear factor kappa-Β ligand (RANKL). Th2 cells, characterized by activated STAT-6 and GATA3 (GATA Binding Protein 3) signaling, are primed by IL-2 and IL-4, and secrete factors e.g., IL-4, IL-10 and IL-13. Regulatory T cells (Tregs) are attracted and primed by factors, e.g., C-C-motif chemokine ligand 22 (CCL22), TGF-β, and IL-2, which activate forkhead box P3, STAT-3 and STAT-5 signaling in these cells. Tregs then secrete factors e.g., IL-4, IL-10, and TGF-β, to regulate osteoblast and osteoclast function, but also activation of T-cells. The same factors (IL-4, IL-10, and TGF-β) are also released by γδ T-cells. CD8⁺ cytotoxic T-cells enhance the pro-inflammatory reaction by releasing factors, e.g., TNF-α and IFN-γ. The different T-cell subsets, are influenced by MSCs and osteoblasts, which secrete / release factors, e.g. TGF-β, IL-4, prostaglandin E2, heme oxygenase 1 (HO-1), RANKL, or delta like ligand 4. Colored arrows depict stimulation and blunt end lines inhibition. Dashed black arrows indicate differentiation processes. CD: Cluster of differentiation; NK: Natural killer; TNF-α: Tumor necrosis factor alpha; IL: Interleukin; IFN: Interferon; CCL: C-C-motif chemokine ligand; TGF-β: Transforming growth factor beta; PGE2: Prostaglandin E2; RANKL: Receptor activator of nuclear factor kappa-Β ligand; STAT: Signal transducer and activator of transcription; Tregs: Regulatory T cells; Foxp3: Forkhead box P3; DLL4: Delta like ligand 4.