Neuronal activity-dependent ATP enhances the pro-growth effect of repair Schwann cell extracellular vesicles by increasing their miRNA-21 loading

Abstract

Functional recovery after peripheral nerve injuries is critically dependent on axonal regeneration. Several autonomous and non-cell autonomous processes regulate axonal regeneration, including the activation of a growth-associated transcriptional program in neurons and the reprogramming of differentiated Schwann cells (dSCs) into repair SCs (rSCs), triggering the secretion of neurotrophic factors and the activation of an inflammatory response. Repair Schwann cells also release pro-regenerative extracellular vesicles (EVs), but is still unknown whether EV secretion is regulated non-cell autonomously by the regenerating neuron. Interestingly, it has been described that nerve activity enhances axonal regeneration by increasing the secretion of neurotrophic factors by rSC, but whether this activity modulates pro-regenerative EV secretion by rSC has not yet been explored. Here, we demonstrate that neuronal activity enhances the release of rSC-derived EVs and their transfer to neurons. This effect is mediated by activation of P2Y receptors in SCs after activity-dependent ATP release from sensory neurons. Importantly, activation of P2Y in rSCs also increases the amount of miRNA-21 present in rSC-EVs. Taken together, our results demonstrate that neuron to glia communication by ATP-P2Y signaling regulates the content of SC-derived EVs and their transfer to axons, modulating axonal elongation in a non-cell autonomous manner.

A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair

“…[ 49 ] In animal models of nerve injury, SCs‐EVs have been confirmed to be effective in promoting regeneration. [ 13a,50 ] Nevertheless, EVs‐based therapies face a significant challenge due to the poor yield and low retention rate of EVs.…”

Schwann cells as a target cell for the treatment of cancer pain

“…Studies have found that neuronal activity enhances the release of extracellular vesicles derived from SCs and transfers them to neurons. This effect is achieved by activating P2Y receptors on SCs after sensory neurons release activity‐dependent ATP (Saquel et al, 2022). The activation of purinergic receptors can lead to the calcium‐dependent release of ATP, UDP, growth factors, and cytokines in SCs, which activate neurons (Patritti‐Cram et al, 2021).…”

Extracellular vesicles: Emerged as a promising strategy for regenerative medicine

“…Moreover, repair SCs (rSCs) could also release pro-regenerative EVs. Neuronal activity enhances the release of rSC-derived EVs and their transfer to neurons via the ATP-P2Y signaling pathway[ 87 ]. Mechanical stimuli could control the intercellular communication between neurons and SCs by changing the composition of miRNA in SC-EVs.…”