Multi-omic characterization of human sural nerves across polyneuropathies

Abstract Diseases of peripheral nerves termed polyneuropathies (PNPs) are common, mechanistically heterogeneous, and challenging to diagnose, but have not been investigated at single cell resolution. Here, we integrated single nuclei transcriptomics of peripheral nerves from 33 human PNP patients and four controls (365,708 nuclei) with subcellular spatial transcriptomics. We identified and spatially validated novel and human-specific markers of myelinating and non-myelinating Schwann cells and unexpectedly heterogeneous perineurial fibroblasts. Nerve-associated leukocytes were diverse with an endoneurial to epineurial macrophage gradient. All PNPs shared a loss of myelinating and an increase in repair Schwann cells and lipid-associated macrophages. Transcriptional changes affected multiple cells outside of the endoneurium across PNPs, suggesting PNPs as ‘pan-nerve diseases’. Spatially, PNPs showed a perineurial hyperplasia and fibrotic dispersion and this was most pronounced in immune-mediated PNPs. We found potential of single cell transcriptomics for supporting the differential diagnosis of PNPs and for their future unbiased diagnostic classification. Significance Statement The first large-scale integrated single cell and spatial transcriptomic characterization of human peripheral nerves identifies novel cell markers and unexpected heterogeneity of perineurial cells, reveals polyneuropathies as ‘pan-nerve diseases’, and shows that single cell transcriptomics hold potential for unbiased nerve disease classification.