Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons

Abstract

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-β1-dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K-phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2-PI3K-p-Akt signalling pathway.

Highly Purified Human Extracellular Vesicles Produced by Stem Cells Alleviate Aging Cellular Phenotypes of Senescent Human Cells

“…Size distribution and concentration measurement were conducted on a second generation nanoparticle tracking analysis (NTA) instrument, the ZetaView (Particle Metrix, Germany) with a 488-nm laser and software ZetaView 8.04.02. Temperature was controlled at 24 C. The data acquisition parameters were set as follows: positions (11), cycles number (1), sensitivity (85), frame rate (30), shutter (70), minimum brightness (20), max size (1,000), and min size (5). All parameters were recommended by the manufacturer for EV analysis.…”

PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

“…Sciatic DRGs (3 biological replicates, pool of 2 mice/replicate) were extracted 24h after sham, sciatic nerve axotomy, laminectomy or dorsal column axotomy surgeries (surgeries were performed as described above), and RNAseq was performed and analysed as we previously described 20 . Sequence reads were aligned to the mm10 mouse reference genome sequence…”

Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

“…We do not know yet whether EV uptake is beneficial or detrimental for neurons, and whether the cell of origin determines its function. Notably, oligodendrocyte-derived EVs can have trophic effects on neurons in vitro [21] and macrophage-derived exosomes, containing functional NADPH oxidase 2 complexes promote axonal regeneration [22]. On the other hand, neuronal activity has been linked to tau propagation [23] and uptake of EVs may at least in part explain this transneuronal spread.…”