Injured Axons Instruct Schwann Cells to Build Constricting Actin Spheres to Accelerate Axonal Disintegration

Abstract

Highlights d Injured axons upregulate PlGF, which activates VEGFR1 in Schwann cells d VEGFR1 activates the formation of constricting actin spheres in Schwann cells d Constricting actin spheres accelerate the disintegration of injured axons d VEGFR1 expression in oligodendrocytes accelerates injured axon disintegration

Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury

“…Although they are unable to fully predict what happens at the whole organ level, primary SC/neuron cocultures have been useful PNS models to investigate the molecular mechanisms involved in axonal regrowth fostered by SCs and remyelination. Moreover, microfluidic devices, which allow the compartmentalization of neuronal cell bodies, axons and myelinating cells, have demonstrated to be useful in in vitro research [15,16].…”

“…The presence of persistent axon fragments inhibits the regeneration of axon branches [21] and leads to delayed axonal regrowth [16,41,42]. We recently showed that after a peripheral nerve lesion, SCs form constricting actomyosin spheres along unfragmented distal cut axons to accelerate their disintegration [16]. Interestingly, this mechanism is triggered by distal cut axons that upregulate the VEGFR1 agonist PlGF by injury-induced local translation, resulting in the activation of a VEGFR1/Pak1/F-actin axis in SCs [16].…”

“…We recently showed that after a peripheral nerve lesion, SCs form constricting actomyosin spheres along unfragmented distal cut axons to accelerate their disintegration [16]. Interestingly, this mechanism is triggered by distal cut axons that upregulate the VEGFR1 agonist PlGF by injury-induced local translation, resulting in the activation of a VEGFR1/Pak1/F-actin axis in SCs [16]. Moreover, after injury myelin in the distal injured axon site breaks down into small intracellular and extracellular fragments and debris.…”

“…Indeed, they are characterized by de-novo expression of genes that include Olig1 and Shh and by the upregulation of many proteins involved in the regeneration process. Among those, (1) c-Jun, the main driver of the SC-dependent repair program, glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), artemin, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 support the survival of injured neurons and promote the regrowth of proximal axons [ 1 , 16 , 18 – 20 ]; (2) leukemia inhibitory factor (LIF), interleukin-1α (IL-1α) and -1β (IL-1β), tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein 1 (MCP-1) initiate the immune response, promote macrophage invasion and activation, blood vessel formation and myelin breakdown [ 1 , 21 – 24 ]; (3) c-Jun, SRY-box 2 (Sox2) and neuregulin 1 (NRG1) are involved in SC morphological changes and axoglial interactions, in the formation of a nerve bridge in case of nerve transection and of the regeneration tracks along which axons regrow; (4) zinc finger E-box-binding homeobox 2 (Zeb2), nuclear factor-kappa B (NF-kB) and histone deacetylases 1 and 2 (HDAC1/2) are involved in the remyelination of the regenerated axon [ 25 – 29 ]. A summary of the main factors involved in the regeneration process is illustrated in Fig.…”

“…To be efficient, the regenerative process requires the generation of a favorable environment that fosters axonal repair. Rapidly after injury, SCs promote the disintegration of distal cut axons [ 16 ] and their clearance, together with invading macrophages [ 38 – 40 ]. The presence of persistent axon fragments inhibits the regeneration of axon branches [ 21 ] and leads to delayed axonal regrowth [ 16 , 41 , 42 ].…”