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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism
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Cell Communication
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Cell Differentiation / drug effects
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Coculture Techniques
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Culture Media, Conditioned / pharmacology*
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / metabolism
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Dinoprostone / pharmacology*
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Gene Expression Regulation / drug effects*
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
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Macrophage Activation / drug effects
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Macrophages / cytology
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Macrophages / drug effects*
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Macrophages / metabolism
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / metabolism*
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Phagocytosis / drug effects
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Primary Cell Culture
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Salmonella enterica / growth & development
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Signal Transduction
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism
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THP-1 Cells
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
Substances
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Culture Media, Conditioned
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Glucose Transporter Type 1
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IDO1 protein, human
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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RNA, Small Interfering
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SLC2A1 protein, human
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Cyclooxygenase 2
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PTGS2 protein, human
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MTOR protein, human
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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SIRT1 protein, human
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Sirtuin 1
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Dinoprostone