Mesenchymal stem cells induce the ramification of microglia via the small RhoGTPases Cdc42 and Rac1

• Published in: Glia 2014-12, Vol.62 (12), p.1932-1942
• Main Authors: Neubrand, Veronika E., Pedreño, Marta, Caro, Marta, Forte-Lago, Irene, Delgado, Mario, Gonzalez-Rey, Elena
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Antigens, CD - metabolism; Brain - cytology; cdc42 GTP-Binding Protein - metabolism; Cell Differentiation; cell shape; Cell Size; Cells, Cultured; colony stimulating factor-1; Culture Media, Conditioned - pharmacology; Cytokines - metabolism; Flavonoids - pharmacology; Genotype & phenotype; Immune system; Lipopolysaccharides - pharmacology; Macrophage Colony-Stimulating Factor - pharmacology; Mesenchymal Stromal Cells - chemistry; Mesenchymal Stromal Cells - physiology; Mice; Mice, Inbred C57BL; Microglia - cytology; Microglia - drug effects; Microglia - physiology; Morphology; neurodegeneration; neuroinflammation; Phagocytosis - physiology; Protein Kinase Inhibitors - pharmacology; rac1 GTP-Binding Protein - metabolism; Signal Transduction - drug effects; Stem cells; Time Factors
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22714

Activated microglia play a central role in the course of neurodegenerative diseases as they secrete cytotoxic substances which lead to neuronal cell death. Understanding the mechanisms that drive activation of microglia is essential to reverse this phenotype and to protect from neurodegeneration. With some exceptions, evidence indicates that changes in cell morphology from a star shape to a round and flat shape accompany the process of activation in microglia. In this study, we investigated the effect of adipose‐tissue‐derived mesenchymal stem cells (ASCs), which exert important anti‐inflammatory actions, in microglia morphology. Microglia exposed to ASCs or their secreted factors (conditioned medium) underwent a cell shape change into a ramifying morphology in basal and inflammatory conditions, similar to that observed in microglia found in healthy brain. Colony‐stimulating factor‐1 secreted by ASCs played a critical role in the induction of this phenotype. Importantly, ASCs reversed the activated round phenotype induced in microglia by bacterial endotoxins. The ramifying morphology of microglia induced by ASCs was associated with a decrease of the proinflammatory cytokines tumor necrosis factor‐α and interleukin‐6, an increase in phagocytic activity, and the upregulation of neurotrophic factors and of Arginase‐1, a marker for M2‐like regulatory microglia. In addition, activation of the phosphoinositide‐3‐kinase/Akt pathway and the RhoGTPases Rac1 and Cdc42 played a major role in the acquisition of this phenotype. Therefore, these RhoGTPases emerge as key players in the ramification of microglia by anti‐inflammatory agents like ASCs, being fundamental to maintain the tissue‐surveying, central nervous system supporting state of microglia in healthy conditions. GLIA 2014;62:1932–1942 Main Points Adipose‐tissue derived mesenchymal stem cells induced microglia ramification, which was CSF‐1 dependent and associated with anti‐inflammatory, neuroprotective properties. The small RhoGTPases Rac1 and Cdc42 played a fundamental role in this process.