Researchers analyzing tissue from human donors with diabetic peripheral neuropathy found that clusters of nonneuronal cells known as Nageotte nodules may mark widespread sensory neuron loss.
The researchers examined dorsal root ganglia (DRG), which house neurons that transmit pain and touch signals from the body to the spinal cord. Nageotte nodules were present in approximately 25% of neurons in patients with diabetic peripheral neuropathy (DPN).
These nodules, first described over a century ago, form when sensory neurons die and are replaced by surrounding support cells. Using histology and spatial transcriptomic analysis on DRG samples from 90 organ donors, the researchers characterized the structure and molecular features of Nageotte nodules. Donors with diabetes, particularly those with DPN or taking neuropathic pain medications—had more nodules compared with nondiabetic individuals.
“We found that 25% of the neurons had a Nageotte nodule morphology in the DPN DRGs, suggesting that a quarter of all sensory neurons are dead in these [patients],” said lead study author Stephanie I. Shiers, of the University of Texas at Dallas, and colleagues.
The nodules were primarily composed of satellite glial cells and nonmyelinating Schwann cells expressing markers such as SOX10, SPP1 (osteopontin), and FABP7. These nodules were intertwined with damaged axons showing signs of attempted regeneration.
Axonal sprouting into the nodules was marked by expression of sensory neuron markers including peripherin and Nav1.7. In one donor, axons expressing the pain-associated protein TRPV1 were also found. These findings suggested that surviving neurons may attempt to regenerate or form new connections, though the functional significance remains unclear.
The axons entering the nodules were not sympathetic fibers, as evidenced by the absence of tyrosine hydroxylase staining. Instead, they appeared to originate from nearby sensory neurons, which often lost their characteristic pseudounipolar shape and developed a multipolar structure with multiple axon branches.
RNA sequencing revealed potential signaling between nodules and adjacent neurons. Notably, osteopontin produced by glial cells may interact with CD44 receptors on neurons—a pathway possibly involved in axonal sprouting or neuronal activation. Elevated levels of phosphorylated eIF4E, a translation regulator linked to pain signaling, were also detected in both neurons and nodules from DPN samples.
Similar structures were observed in cultured human sensory neurons, which developed multipolar shapes and axonal buds resembling Nageotte nodules.
The findings provided insights into the mechanisms of sensory neuron degeneration in diabetic neuropathy and indicated that support cells may play a role in disease progression. Identifying the molecular pathways involved could inform future research on neuroprotection and pain regulation in diabetes.
Full disclosures can be found in the study.
Source: Nature Communications
