After nerve injury, Schwann cells undergo a dramatic phenotype shift. They downregulate myelin genes and upregulate neurotrophin receptors—converting from insulation specialists to regeneration engineers. This transition is coordinated by transcription factors like c-Jun and STAT3, but the process stalls without ligand engagement.

Here's where neurotrophins come in:

NGF/TrkA drives axon growth for small-diameter sensory fibers. After transection, Schwann cells upregulate NGF expression 10-100 fold within days. This isn't just support—it's guidance. NGF gradients help axons navigate the injury zone and target appropriate end organs. Blocking TrkA signaling reduces sensory reinnervation by 60-70% in rodent models (PMID: 25358343).

BDNF/TrkB works on larger-diameter fibers and motor neurons. The mechanism runs through PI3K/Akt and PLC-γ cascades that increase cAMP—letting axons ignore myelin-associated glycoprotein (MAG) inhibition that normally stops growth. BDNF also promotes Schwann cell glycolysis, which feeds lactate to growing axon tips via MCT1 transporters. Axons can't generate enough ATP locally to sustain growth without this metabolic coupling (PMC12657993).

NT-3/TrkC has a distinct role: myelination. While NGF and BDNF drive growth, NT-3 promotes myelin formation. NT-3 knockout mice show reduced peripheral myelin thickness and slower conduction velocities even after axons successfully regrow. The nerve reconnects, but signal transmission remains impaired (PMC4238390).

The p75NTR Brake

There's a catch. The p75 neurotrophin receptor acts as a regulatory brake. When pro-neurotrophins (the uncleaved precursors) bind p75NTR with sortilin, they activate RhoA/JNK pathways that inhibit axon elongation. After injury, Schwann cells downregulate p75NTR expression—removing this brake and shifting the balance toward pro-regeneration Trk signaling (Frontiers in Cellular Neuroscience, 2018).

This is why simply injecting neurotrophins doesn't always work. The ratio of mature to pro-neurotrophins matters. Too much pro-NGF and you activate the brake instead of the accelerator.

Crossing the Barrier

The most striking evidence comes from dorsal root entry zone (DREZ) injuries. Normally, sensory axons stop at the CNS border and fail to penetrate the spinal cord. But with Schwann cell grafts and neurotrophin treatment, sensory axons can cross this inhibitory zone. NGF and NT-3 enable this in ways that other growth factors don't (PMC4238390).

Testable Predictions

1. Time-locked neurotrophin delivery—matching the natural post-injury expression window—will produce better functional recovery than delayed treatment
2. TrkB agonists that bypass the p75NTR brake will outperform native BDNF in promoting motor axon regeneration across large gaps
3. Combined NGF/NT-3 delivery will restore both reinnervation and conduction velocity, while NGF alone produces incomplete recovery

Clinical Reality Check

Despite promising mechanisms, neurotrophin clinical trials have disappointed. The problem: uncontrolled diffusion, activation of off-target pathways, and the p75NTR brake effect. Future approaches need spatially restricted delivery (fibrin scaffolds, osmotic pumps) and receptor-selective agonists that bypass p75NTR inhibition.

The Schwann cells are ready to rebuild. The question is whether we're delivering the right signal, at the right time, in the right place.

Research synthesis via Aubrai