Very proud that our human PNS atlas is finally published in @NatureComms. We found perineurial hyperplasia and lipid-associated nerve macrophages in #polyneuropathies. Explore: pns-atlas.mzhlab.com A tweetorial 1/13 doi.org/10.1038/s41467-025-6…

2/13 Polyneuropathies (PNP) are among the most common neurological diseases (~4%, but the underlying causes remain unclear in many patients (~20-30%). We used state of the art single cell technologies to better characterize sural nerves in health and disease.

3/13 We combined single nuclei sequencing of 33 human polyneuropathy patients and four controls (365,708 nuclei) with subcellular spatial transcriptomics (#Xenium).

4/13 Single nuclei sequencing dissected cell populations in the sural nerve in great detail, replicating and extending cell populations identified in single cell rodent studies. Interestingly, we identified transcriptionally heterogeneous perineurial fibroblasts.

5/13 We identified novel and human-specific nerve cell type markers using snRNA-seq, which were validated using spatial transcriptomics

6/13 Integrating spatial transcriptomics with snRNA-seq provided an unbiased histological annotation of peripheral nerve cells.

7/13 Human peripheral nerves contained complex immune cells, including a plethora of myeloid cell populations. Macrophage clusters exhibited an endoneurial to epineurial gradient, previously described in rodents.

8/13 PNPs shared a loss of myelinating Schwann cells (mySC) and an increase in repair and damaged Schwann cells (repairSC, damageSC) and an increase in endoneurial lipid-associated macrophages (LAM).

9/13 LAM markers (SPP1/osteopontin, PLIN2, CD36, FABP5) colocalized histologically with myelin and BODIPY (labels neutral lipids). LAM thus likely has myelin-phagocytizing capacity.

10/13 immune, repairSC and periC3 cluster also correlated with clinical disease severity (INCAT score) and myelin thickness (g-ratio). (using CNA @ilyakorsunsky

11/13 Transcriptional changes affected multiple cells outside of the endoneurium across PNPs, suggesting PNPs as pan-nerve diseases (using miloDE from @MarioniLab )

12/13 PNPs showed previously unknown perineurial hyperplasia and fibrotic dispersion and this was most pronounced in immune-mediated PNPs.