Single-cell atlas of neuroma-induced DRG remodeling reveals intervention-specific glial and immune programs.

Peripheral nerve injury caused by cut, crush, or excessive stretch can lead to disordered regeneration and painful neuroma formation. Regrowing axons may terminate in a swollen, hypersensitive nerve stump, producing pain that can outweigh sensory or motor deficits. Despite the frequency of neuromas, treatment outcomes remain inconsistent, and the mechanisms that initiate and sustain neuroma-associated pain are poorly understood. A proximal nerve crush performed upstream of a neuroma or transection may reshape axonal growth and interrupt retrograde injury signaling, potentially promoting a regenerative, pain-resolving state. However, its long-term effects on dorsal root ganglion (DRG) programs remain unclear. Here, we use single-cell RNA sequencing to build an atlas of DRG remodeling after neuroma-forming injury and compare it with two interventions: proximal nerve crush and nerve resection. By resolving transcriptional responses across sensory neurons, satellite glial cells, Schwann cells, and macrophages, we identify intervention-specific glial, neuronal, and immune programs that distinguish regenerative from persistent injury-associated states and nominate pathways that may guide mechanism-based therapies for painful neuromas.