Pathological Abnormalities of Painful Diabetic Neuropathy in The Human Dorsal Root Ganglion

Patients with diabetes mellitus can experience spontaneous sharp and burning pain sensation in the absence of tissue injury. This phenotype is caused by diabetic insults such as reactive oxygen species, excessive polyols, hypoxia, and microvascular issues that lead to neurodegeneration of nociceptive sensory neurons and their axons in the dorsal root ganglia (DRGs). To understand the morphological and molecular underpinnings of how these sensory neurons contribute to diabetic pain, we conducted histological assays and spatial RNA sequencing on human DRGs procured from organ donors with painful diabetic neuropathy (DPN). We note extreme anatomical abnormalities in the DPN DRG samples including the presence of peripherin-positive dystrophic axons and Nageotte nodules, a structure that was discovered over a hundred years ago and has been described as a cluster of satellite glial cells at the site of decomposed sensory neurons. Interestingly, we identified a neuroma-like structure composed of nociceptive axons (Nav1.8+) that is intertwined with the cells forming Nageotte nodules. To understand what cell-types form these structures and how they may interact with the surviving nociceptors, we conducted spatial RNA sequencing on the DPN DRGs and found enrichment of genes for satellite glial cell, macrophages, fibroblasts, and Schwann cells localized at Nageotte nodules which were abundant in ligands that can interact with receptors found on local neurons. These ligand-receptor interactions may represent mechanistic drivers of diabetic neuropathy and evidence new therapeutic intervention opportunities for the treatment of diabetic pain. This work was supported by the U19NS130608 grant.