Abstract
Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS) and are known to be involved in various pathophysiological processes, such as diabetic neuropathy and nerve regeneration, through neurotrophin signaling. Such glial trophic support to axons, as well as neuronal survival/death signaling, has previously been linked to the p75 neurotrophin receptor (p75NTR) and its co-receptor Sortilin. Recently, SC-derived extracellular vesicles (EVs) were shown to be important for axon growth and nerve regeneration, but cargo of these glial cell-derived EVs has not yet been well-characterized. In this study, we aimed to characterize signatures of small RNAs in EVs derived from wild-type (WT) SCs and define differentially expressed small RNAs in EVs derived from SCs with genetic deletions of p75NTR (Ngfr−/−) or Sortilin (Sort1−/−). Using RNA sequencing, we identified a total of 366 miRNAs in EVs derived from WT SCs of which the most highly expressed are linked to the regulation of axonogenesis, axon guidance and axon extension, suggesting an involvement of SC EVs in axonal homeostasis. Signaling of SC EVs to non-neuronal cells was also suggested by the presence of several miRNAs important for regulation of the endothelial cell apoptotic process. Ablated p75NTR or sortilin expression in SCs translated into a set of differentially regulated tRNAs and miRNAs, with impact in autophagy and several cellular signaling pathways such as the phosphatidylinositol signaling system. With this work, we identified the global expression profile of small RNAs present in SC-derived EVs and provided evidence for a regulatory function of these vesicles on the homeostasis of other cell types of the PNS. Differentially identified miRNAs can pave the way to a better understanding of p75NTR and sortilin roles regarding PNS homeostasis and disease.
Highlights
The structural homeostasis is challenging for sensory neurons, whose axons may extend up to more than one meter in humans and with an axonal volume reaching over a thousand times that of the cell body
A body of evidence indicates that Schwann cells (SCs) support the axonal maintenance and regenerative responses by diverse mechanisms of cell–cell communication: SCs regulate a wide variety of axonal functions [2], including passive functions associated with myelin formation with subsequent increase in the conduction velocity [3], and more active roles such as enrichment of sodium channels at the nodes of Ranvier [4], specification of the internodal distance [5] as well as metabolic maintenance of the axonal compartment [6]
Regulate cell death/survival, we investigated if lack of the interacting partner sortilin could affect the viability of SCs in vitro
Summary
The structural homeostasis is challenging for sensory neurons, whose axons may extend up to more than one meter in humans and with an axonal volume reaching over a thousand times that of the cell body. The regulation of neuronal form and function by SCs has been found to be mediated by different forms of intercellular communication, including coupling via local currents in the periaxonal space, paracrine signaling (e.g., ATP, glutamate) and physical coupling via adhesion molecules and gap junctions [7] In addition to these classic mechanisms, recent findings suggest the occurrence of lateral molecular cargo transfer mediated by secreted extracellular vesicles (EVs) from SCs to axons [8,9,10]. EVs constitute mainly two types of vesicles: exosomes and microvesicles, which are generated by all cell types and derive from multivesicular bodies or through bubbling of the plasma membrane, respectively [11] They contain, and are able to transport, proteins, lipids and genetic material such as DNA and RNA with variations in cargo composition depending on, e.g., the age, metabolic state and type of the donor cell [12]. In addition to export of cell waste [13], EV-mediated intercellular signaling is an essential component of regulatory neuro-glial communication
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