Extracellular vimentin is a novel axonal growth facilitator for functional recovery in spinal cord-injured mice

Abstract

Vimentin, an intermediate filament protein, is an intracellular protein that is involved in various cellular processes. Several groups have recently reported that vimentin also appears in the extracellular space and shows novel protein activity. We previously reported that denosomin improved motor dysfunction in mice with a contusive spinal cord injury (SCI). At the injured area, astrocytes expressing and secreting vimentin were specifically increased, and axonal growth occurred in a vimentin-dependent manner in denosomin-treated mice. However, the axonal growth that was induced by extracellular vimentin was only investigated in vitro in the previous study. Here, we sought to clarify whether increased extracellular vimentin can promote the axonal extension related to motor improvement after SCI in vivo. Extracellular vimentin treatment in SCI mice significantly ameliorated motor dysfunction. In vimentin-treated mice, 5-HT-positive axons increased significantly at the rostral and central areas of the lesion, and the total axonal densities increased in the central and caudal parts of the lesioned area. This finding suggests that increased axonal density may contribute to motor improvement in vimentin-treated mice. Thus, our in vivo data indicate that extracellular vimentin may be a novel neurotrophic factor that enhances axonal growth activity and motor function recovery after SCI.

Release of astroglial vimentin by extracellular vesicles: Modulation of binding and internalization of C3 transferase in astrocytes and neurons

“…The relevance of the first mechanism, however, might only become apparent when astrocytes are pharmacologically stimulated in vivo to secrete vimentin (Teshigawara et al, 2013) or by direct intrathecal administration of vimentin (Shigyo & Tohda, 2016) since the intrinsic capacity of the CNS to regenerate is very limited. We do not know yet which exosome/recipient cell interactions apply to promote the interaction with C3bot.…”

“…In this context, it is unclear whether vimentin is essential for cellular uptake of C3bot as suggested from the lack of axonotrophic effects of C3bot in Vim −/− cultures (Adolf et al, 2016) or whether it serves a supporting role in other cell types, for example, in astrocytes. Besides its well-known intracellular localization as part of the intermediate filament network in astrocytes that becomes upregulated following SCI (Ridet, Malhotra, Privat, & Gage, 1997), evidence emerges that vimentin might be secreted from astrocytes following injury to the spinal cord (Teshigawara et al, 2013) and to even functionally interact with regenerating fibers to speed up motor recovery (Shigyo & Tohda, 2016). In contrast, the glial scar mostly formed by astrocytes involves deposition of regeneration-inhibitory extracellular matrix proteins such as chondroitin sulfate proteoglycans (CSPGs), laminin, and others (for review, see Orr & Gensel, 2018) and is generally considered as an obstacle for neuronal regeneration.…”

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

“…Astrocyte clues such as secreted factors (secretome) and cell-cell contact signals are essential for proper development, maintenance, and functioning of individual neurons, as well as for the wiring of the central nervous system (CNS) by controlling axonal guidance and dendritic complexity [1][2][3].…”

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

“…Astrocyte clues such as secreted factors (secretome) and cell-cell contact signals are essential for proper development, maintenance, and functioning of individual neurons, as well as for the wiring of the central nervous system (CNS) by controlling axonal guidance and dendritic complexity [1]- [3].…”