Schwann cell‐derived exosomes enhance axonal regeneration in the peripheral nervous system

Abstract

Axonal regeneration in the peripheral nervous system is greatly supported by Schwann cells (SCs). After nerve injury, SCs dedifferentiate to a progenitor-like state and efficiently guide axons to their original target tissues. Contact and soluble factors participate in the crosstalk between SCs and axons during axonal regeneration. Here we show that dedifferentiated SCs secrete nano-vesicles known as exosomes which are specifically internalized by axons. Surprisingly, SC-derived exosomes markedly increase axonal regeneration in vitro and enhance regeneration after sciatic nerve injury in vivo. Exosomes shift the growth cone morphology to a pro-regenerating phenotype and decrease the activity of the GTPase RhoA, involved in growth cone collapse and axon retraction. Altogether, our work identifies a novel mechanism by which SCs communicate with neighboring axons during regenerative processes. We propose that SC exosomes represent an important mechanism by which these cells locally support axonal maintenance and regeneration after nerve damage.

Extracellular vesicles and intercellular communication within the nervous system

“…In this context, Lopez-Verrilli and colleagues demonstrated that Schwann cell-derived EVs stimulated axonal growth and regeneration after nerve damage in vitro when taken up by adjacent sensory neurons (ref. 19 and Figure 2B). After internalization in damaged axons, Schwann cell-derived EVs modulated growth cone morphology and downregulated growth inhibitors, such as RhoA GTPase, both in culture and in vivo.…”

“…EVs are released from virtually all cell types in the brain, including neural stem/progenitor cells (5,6), neurons (7)(8)(9), astrocytes (9-13), oligodendrocytes (13)(14)(15), and microglia (16,17) as well as Schwann cells and neurons in the peripheral nervous system (18)(19)(20). A schematic overview of potential EV-mediated interactions in the nervous system is provided in Figure 1.…”

PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy

“…67 In the peripheral nervous system, Schwann cells release exosomes that are specifically internalized by axons, resulting in increased axonal regeneration after sciatic nerve injury. 68 Additionally, exosomes derived from multipotent mesenchymal stromal cells (MSCs) improve the functional recovery of neurons after stroke in a rat model. 69 Notably, our present findings demonstrate that astrocytes and fibroblasts derived from mice overexpressing PRNP exhibited higher levels of secreted exosomes, indicating a general role for PRNP in regulating exosome secretion independent of cell type.…”

p75 neurotrophin receptor evades the endolysosomal route, favouring multivesicular bodies specialised for exosomal release in neuronal cells

“…Indeed, the role of exosomes as immune-modulators and regulators of cancer progression is extensively documented (Vlassov et al, 2012). Furthermore, our recent publication indicates that Schwann cells release exosomes containing p75 and that these vesicles enhanced axonal regeneration (Lopez-Verrilli et al, 2013).…”