Spatial transcriptomic profiling of human paravertebral sympathetic chain ganglia reveals diabetes-induced...

The paravertebral sympathetic chain ganglia (SCG) are autonomic ganglia critical for regulating the "fight-or-flight" response. Symptoms of sympathetic dysfunction are prevalent in diabetes, affecting up to 90% of patients. The molecular and cellular composition of the human SCG and its alteration in diabetes remains poorly defined. To address this gap, we performed spatial transcriptomic profiling of lumbar SCGs from diabetic and non-diabetic organ donors. We identified 3 three distinct neuronal populations, two noradrenergic (NA1 and NA2) and one cholinergic (CHO), based on tyrosine hydroxylase (TH) and SLC18A3 expression, respectively. We also characterized 9 non-neuronal populations consisting of Schwann cells, immune cells, fibroblasts, adipocytes, and endothelial cells. In diabetic SCGs, we observed a significant loss of myelinating Schwann cells and a phenotypic shift of cholinergic neurons toward a noradrenergic identity. Additionally, diabetes was associated with a significant reduction in the transcripts of vasodilatory neuropeptides, such as VIP and CALCA, suggesting a mechanism for impaired vascular control. Upstream regulator analysis highlighted altered neurotrophic signaling in diabetes, with enhanced NGF/TRKA and diminished BDNF/TRKB activity, potentially driven by target-derived cues. Comparison between SCG and dorsal root ganglia (DRG) neurons revealed ganglia-specific genes, like SCN3A and NPY (SCG) versus SCN10A and GPX1 (DRG), offering specific therapeutic targets for autonomic dysfunction or pain. Our findings provide a transcriptomic characterization of human SCG, revealing molecular signatures that underlie diabetic autonomic dysfunction. This work lays a foundation for the development of therapies to restore sympathetic function and avoid unintended autonomic effects in the development of analgesics.