Mesenchymal stem cells (MSCs) are speculated to act at macrophage-injury interfaces to mediate efficient repair. To explore this facet in-depth this study evaluates the influence of MSCs on human macrophages existing in distinct functional states. MSCs promoted macrophage differentiation, enhanced respiratory burst and potentiated microbicidal responses in naïve macrophages (Mφ). Functional attenuation of inflammatory M1 macrophages was associated with a concomitant shift towards alternatively activated M2 state in MSC-M1 co-cultures. In contrast, alternate macrophage (M2) activation was enhanced in MSC-M2 co-cultures. Elucidation of key macrophage metabolic programs in Mo/MSC, M1/MSC and M2/MSC co-cultures indicated changes in Glucose transporter1 (GLUT1 expression/glucose uptake, IDO1 protein/activity, SIRTUIN1 and alterations in AMPK and mTOR activity, reflecting MSC-instructed metabolic shifts. Inability of Cox2 knockdown MSCs to attenuate M1 macrophages and their inefficiency in instructing metabolic shifts in polarized macrophages establishes a key role for MSC-secreted PGE2 in manipulating macrophage metabolic status and plasticity. Functional significance of MSC-mediated macrophage activation shifts was further validated on human endothelial cells prone to M1 mediated injury. In conclusion, we propose a novel role for MSC secreted factors induced at the MSC-macrophage interface in re-educating macrophages by manipulating metabolic programs in differentially polarized macrophages.
Clinically reported reparative benefits of mesenchymal stromal cells (MSCs) are majorly attributed to strong immune-modulatory abilities not exactly shared by fibroblasts. However, MSCs remain heterogeneous populations, with unique tissue-specific subsets, and lack of clear-cut assays defining therapeutic stromal subsets adds further ambiguity to the field. In this context, in-depth evaluation of cellular characteristics of MSCs from proximal oro-facial tissues: dental pulp (DPSCs) and periodontal ligament (PDLSCs) from identical donors provides an opportunity to evaluate exclusive niche-specific influences on multipotency and immune-modulation. Exhaustive cell surface profiling of DPSCs and PDLSCs indicated key differences in expression of mesenchymal (CD105) and pluripotent/multipotent stem cell–associated cell surface antigens: SSEA4, CD117, CD123 and CD29. DPSCs and PDLSCs exhibited strong chondrogenic potential, but only DPSCs exhibited adipogenic and osteogenic propensities. PDLSCs expressed immuno-stimulatory/immune-adhesive ligands like HLA-DR and CD50, upon priming with IFNγ, unlike DPSCs, indicating differential response patterns to pro-inflammatory cytokines. Both DPSCs and PDLSCs were hypo-immunogenic and did not elicit robust allogeneic responses despite exposure to IFNγ or TNFα. Interestingly, only DPSCs attenuated mitogen-induced lympho-proliferative responses and priming with either IFNγ or TNFα enhanced immuno-modulation capacity. In contrast, primed or unprimed PDLSCs lacked the ability to suppress polyclonal T cell blast responses. This study indicates that stromal cells from even topographically related tissues do not necessarily share identical MSC properties and emphasizes the need for a thorough functional testing of MSCs from diverse sources with respect to multipotency, immune parameters and response to pro-inflammatory cytokines before translational usage.
Variations in placental TNF-α protein expression noted at different trimesters may suggest gestational age specific roles for the cytokine. The increase in TNF-α protein expression observed in the second trimester may be involved in upregulating synthesis of MMP and in augmenting apoptosis of vascular smooth muscle cells of the spiral arteries. A failure in this second trimester increase in TNF-α protein could contribute to gestational compromise.
Results suggest that chlamydial infection leads to upregulation of COX-2 in C. trachomatis-positive recurrent spontaneous aborters, which probably mediates increased prostaglandin synthesis.
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