Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 16 February 2020 / Approved: 17 February 2020 / Online: 17 February 2020 (15:53:24 CET)

A peer-reviewed article of this Preprint also exists.

Luarte, A.; Henzi, R.; Fernández, A.; Gaete, D.; Cisternas, P.; Pizarro, M.; Batiz, L.F.; Villalobos, I.; Masalleras, M.; Vergara, R.; Varas-Godoy, M.; Abarzua-Catalan, L.; Herrera-Molina, R.; Lafourcade, C.; Wyneken, U. Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity. Cells 2020, 9, 930. Luarte, A.; Henzi, R.; Fernández, A.; Gaete, D.; Cisternas, P.; Pizarro, M.; Batiz, L.F.; Villalobos, I.; Masalleras, M.; Vergara, R.; Varas-Godoy, M.; Abarzua-Catalan, L.; Herrera-Molina, R.; Lafourcade, C.; Wyneken, U. Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity. Cells 2020, 9, 930.

Journal reference: Cells 2020, 9, 930
DOI: 10.3390/cells9040930

Abstract

In the last 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) which 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 and 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.

Subject Areas

microRNAs; exosomes; astrocytes; hippocampal neurons; dendritic complexity

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