Basic fibroblast growth factor accelerates myelin debris clearance through activating autophagy to facilitate early peripheral nerve regeneration

Abstract

The successful removal of damaged myelin sheaths during Wallerian degeneration (WD) is essential for ensuring structural remodelling and functional recovery following traumatic peripheral nerve injury (PNI). Recent studies have established that autophagy involves myelin phagocytosis and cellular homoeostasis, and its disorder impairs myelin clearance. Based on the role of basic fibroblast growth factor (bFGF) on exerting neuroprotection and angiogenesis during nerve tissue regeneration, we now explicitly focus on the issue about whether the therapeutic effect of bFGF on supporting nerve regeneration is closely related to accelerate the autophagic clearance of myelin debris during WD. Using sciatic nerve crushed model, we found that bFGF remarkedly improved axonal outgrowth and nerve reconstruction at the early phase of PNI (14 days after PNI). More importantly, we further observed that bFGF could enhance phagocytic capacity of Schwann cells (SCs) to engulf myelin debris. Additionally, this enhancing effect is accomplished by autophagy activation and the increase of autophagy flux by immunoblotting and immune‐histochemical analyses. Taken together, our data suggest that the action of bFGF on modulating early peripheral nerve regeneration is closely associated with myelin debris removal by SCs, which might result in SC‐mediated autophagy activation, highlighting its insight molecular mechanism as a neuroprotective agent for repairing PNI.

Delivery of Basic Fibroblast Growth Factor Through an In Situ Forming Smart Hydrogel Activates Autophagy in Schwann Cells and Improves Facial Nerves Generation via the PAK-1 Signaling Pathway

“…Using the rat FNI model, we found that P-bFGF promoted facial nerve repair by 1) maintaining the survival of nerve cells and inhibiting their apoptosis, 2) activating the autophagy of SCs and promoting the removal of myelin debris, and 3) facilitating axon growth and remyelination. These were consistent with previous studies on other peripheral nerve injuries (Wang et al, 2003;Pollak et al, 2014;Jiang et al, 2021). Through in vitro experiments, we found that the molecular mechanism underlying the positive effect of P-bFGF involved the activation of the PAK1 signaling pathway.…”

“…Patients often suffer from partial or permanent disability in sensory and motor nerve function. Exogenous bFGF can promote FNI repair (Li et al, 2018;Jiang et al, 2021), but maintaining the release of bFGF at the appropriate location and time is a major obstacle to effective therapy. We used poloxamer thermosensitive hydrogel with excellent biocompatibility as the carrier.…”

“…Additionally, the protein was released slowly, resulting in a lasting bFGF therapy for FNI. Additionally, previous studies have also shown that the role of bFGF in the regulation of early peripheral nerve regeneration was closely related to the SC-mediated autophagy activation to remove myelin debris (Jiang et al, 2021).…”

BASHY Dye Platform Enables the Fluorescence Bioimaging of Myelin Debris Phagocytosis by Microglia during Demyelination

“…Instead, we see that our fluorescent probe stains a small percentage of initially formed non-compact Qd9-labeled structures but essentially co-localizes with Iba1-positive myelinphagocytosing cells, thus emerging as a promising fluorescent dye for the brain imaging of amoeboid phagocytic microglia (foamy cells) based on its efficacy in labeling myelin debris. Apart from the available markers for intact myelin fibers, myelin debris at the final stage of myelin degradation has been commonly stained using Oil Red O dye [45], which is a non-specific marker that stains for general lipids [46], or tagged with pHRODO reagent to perform myelin debris engulfment assays [47]. A recent study also uses the lipophilic Nile Red dye as a marker to identify changes in the composition and/or polarity of myelin lipids in tissue sections following demyelination.…”

Capacity of astrocytes to promote axon growth in the injured mammalian central nervous system

“…Microglia promote axon sprouting, through the proposed mechanism of phagocytosing myelin debris ( Jiang et al, 2019 ). While microglia and monocyte-derived macrophages are the principal phagocytic cells in the injured CNS, reactive astrocytes can also become highly phagocytic by expressing phagocytic receptors and activation of phagocytic pathways early after spinal cord injury, traumatic brain injury, and brain ischemia ( Morizawa et al, 2017 ; Konishi et al, 2020 ; Wang J. et al, 2020 ; Jiang et al, 2021 ; Zhou et al, 2021 ; Wan et al, 2022 ). Astrocytes can respond to neighboring damaged neurons through sensing and removal of cell debris in injured tissue, in a process that involves engulfment of debris in acidic endocytic vesicles directed toward lysosome for degradation ( Wakida et al, 2018 ; Wang S. et al, 2020 ; Wan et al, 2022 ).…”