Abstract
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.
Highlights
Mesenchymal stem cells (MSCs) are speculated to act at macrophage-injury interfaces to mediate efficient repair
THP-1 monocytes are more phagocytic as compared to macrophages which evolve to perform more specialized antigen presenting cell (APC) functions
A decrease in phagocytic index was noted in Phorbol 12-myristate 13-acetate (PMA) differentiated macrophages as compared to THP-1 monocytes as reported
Summary
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. Functional attenuation of inflammatory M1 macrophages was associated with a concomitant shift towards alternatively activated M2 state in MSC-M1 co-cultures. Macrophages shift gears oscillating between pro-inflammatory M1 and debris-scavenging/tissue-remodeling alternatively activated M2 states. Mechanistic insights from the study indicate a two-way interaction between MSCs and macrophages, wherein MSC secreted factors induced at the MSC-macrophage interface instruct critical metabolic switches in M1 and M2 macrophages which are known to exist in distinct bioenergetic states. Observations discussed in the manuscript raise challenging questions regarding the immune-modulatory plasticity of MSCs when interfaced with distinct macrophage activation states
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