Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 4; p. 930
• Main Authors: Luarte, Alejandro, Henzi, Roberto, Fernández, Anllely, Gaete, Diego, Cisternas, Pablo, Pizarro, Matias, Batiz, Luis Federico, Villalobos, Isabel, Masalleras, Matias, Vergara, Rodrigo, Varas-Godoy, Manuel, Abarzua-Catalan, Lorena, Herrera-Molina, Rodrigo, Lafourcade, Carlos, Wyneken, Ursula
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10-04-2020; MDPI
• Subjects: Animals; Astrocytes; Astrocytes - cytology; Astrocytes - metabolism; Bioinformatics; Biotechnology; Cell Differentiation - physiology; Cells, Cultured; Dendrites - metabolism; dendritic complexity; exosomes; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Fructose-Bisphosphate Aldolase - metabolism; hippocampal neurons; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Immunoglobulins; Laboratory animals; Membranes; MicroRNAs; MicroRNAs - metabolism; miRNA; Morphogenesis; Neurons; Nucleotide sequence; Plasmids; Pregnancy; Proteins; Rats; Rats, Sprague-Dawley; Zebrin II; microRNAs; astrocytes; dendritic complexity; exosomes; hippocampal neurons
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9040930

In the last few decades, it has been established that astrocytes play key roles in the regulation of neuronal morphology. However, the contribution of astrocyte-derived small extracellular vesicles (sEVs) to morphological differentiation of neurons has only recently been addressed. Here, we showed that cultured astrocytes expressing a GFP-tagged version of the stress-regulated astrocytic enzyme Aldolase C (Aldo C-GFP) release small extracellular vesicles (sEVs) that are transferred into cultured hippocampal neurons. Surprisingly, Aldo C-GFP-containing sEVs (Aldo C-GFP sEVs) displayed an exacerbated capacity to reduce the dendritic complexity in developing hippocampal neurons compared to sEVs derived from control (i.e., GFP-expressing) astrocytes. Using bioinformatics and biochemical tools, we found that the total content of overexpressed Aldo C-GFP correlates with an increased content of endogenous miRNA-26a-5p in both total astrocyte homogenates and sEVs. Notably, neurons magnetofected with a nucleotide sequence that mimics endogenous miRNA-26a-5p (mimic 26a-5p) not only decreased the levels of neuronal proteins associated to morphogenesis regulation, but also reproduced morphological changes induced by Aldo-C-GFP sEVs. Furthermore, neurons magnetofected with a sequence targeting miRNA-26a-5p (antago 26a-5p) were largely resistant to Aldo C-GFP sEVs. Our results support a novel and complex level of astrocyte-to-neuron communication mediated by astrocyte-derived sEVs and the activity of their miRNA content.