Mesenchymal stem cells induce the ramification of microglia via the small RhoGTPases Cdc42 and Rac1 Neubrand, Veronika Elisabeth Pedreño, Marta Caro, Marta Forte-Lago, Irene Delgado, Mario González-Rey, Elena Cell shape Neurodegeneration Neuroinflammation Colony stimulating factor-1 This is the peer reviewed version of the following article: Neubrand VE, Pedreño M, Caro M, Forte-Lago I, Delgado M, Gonzalez-Rey E. Mesenchymal stem cells induce the ramification of microglia via the small RhoGTPases Cdc42 and Rac1. Glia. 2014 Dec;62(12):1932-42, which has been published in final form at https://onlinelibrary.wiley.com/doi/10.1002/glia.22714. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. Accepted version is under embargo until July 4th, 2015. 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 pro-inflammatory cytokines TNFalpha and IL6, an increase in phagocytic activity, and the upregulation of neurotrophic factors and of Arginase-1, a marker for M2-like regulatory microglia. Moreover, activation of the phosphoinositide-3-kinase/Akt pathway and the RhoGTPases Rac1 and Cdc42 played a major role in the acquisition of this anti-inflammatory phenotype. Therefore, these RhoGTPases emerge as key players in the ramification and deactivation of microglia by anti-inflammatory agents like ASCs, being fundamental to maintain the tissue-surveying, CNS supporting state of microglia in healthy conditions. 2024-01-02T12:03:49Z 2024-01-02T12:03:49Z 2014 info:eu-repo/semantics/article Glia 62: 1932–1942 https://hdl.handle.net/10481/86484 10.1002/glia.22714 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ info:eu-repo/semantics/openAccess Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Wiley