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

Alejandro Luarte; Henzi, Roberto; Fernández, Anllely; Gaete, Diego; Cisternas, Pablo; Pizarro, Matias; Bátiz, Luis F.; Villalobos, Isabel; Masalleras, Matías; Vergara, Rodrigo C.; Varas-Godoy, Manuel; Abarzua-Catalan, Lorena; Herrera-Molina, Rodrigo; Lafourcade, Carlos; Wyneken, U

Keywords: astrocytes, hippocampal neurons, micrornas, exosomes, dendritic complexity

Abstract

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.

Más información

Título de la Revista: CELLS
Volumen: 9
Fecha de publicación: 2020
Página de inicio: 930
Página final: 930
Notas: WOS