Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies

  • Nat Commun. 2025 Aug 23;16(1):7872. doi: 10.1038/s41467-025-62964-8.
Michael Heming  #  1 ,  Anna-Lena Börsch  #  1 ,  Jolien Wolbert  #  1 ,  Christian Thomas  2 ,  Anne K Mausberg  3 ,  Fabian Szepanowski  3 ,  Bianca Eggert  3 ,  I-Na Lu  1 ,  Julia Tietz  1 ,  Finja Dienhart  1 ,  Maja Meschnark  1 ,  Jan-Kolja Strecker  4 ,  Michael Glatza  2 ,  Carolina Thomas  5 ,  Noemi Gmahl  1 ,  Christine Dambietz  1 ,  Michael Müther  6 ,  Anne-Kathrin Uerschels  7 ,  Kathy Keyvani  8 ,  Jens Minnerup  4 ,  Kathrin Doppler  9 ,  Nurcan Üçeyler  9 ,  Julieta Aprea  10 ,  Andreas Dahl  10 ,  Ruth Stassart  5 ,  Robert Fledrich  11 ,  Heinz Wiendl  12 ,  Claudia Sommer  9 ,  Mark Stettner  3 ,  Gerd Meyer Zu Hörste  13
Affiliations
  • 1. Department of Neurology, University Hospital Münster, Münster, Germany.
  • 2. Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • 3. Department of Neurology, Center for Translational Neuro- and Behavioural Sciences (C-TNBS), University Hospital Essen, Essen, Germany.
  • 4. Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany.
  • 5. Paul-Flechsig-Institute of Neuropathology, University Hospital Leipzig, Leipzig, Germany.
  • 6. Department of Neurosurgery, University Hospital Münster, Münster, Germany.
  • 7. Department of Neurosurgery, University Hospital Essen, Essen, Germany.
  • 8. Department of Neuropathology, University Hospital Essen, Essen, Germany.
  • 9. Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
  • 10. DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, Dresden University of Technology, Dresden, Germany.
  • 11. Institute of Anatomy, University of Leipzig, Leipzig, Germany.
  • 12. Clinic of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany.
  • 13. Department of Neurology, University Hospital Münster, Münster, Germany. [email protected].
  • # Contributed equally.
PMID: 40849297 DOI: 10.1038/s41467-025-62964-8
Abstract

Diseases affecting multiple peripheral nerves, termed polyneuropathies (PNPs), are common, mechanistically heterogeneous, and their causes are challenging to identify. Here, we integrated single-nucleus transcriptomics of peripheral nerves from 33 human PNP patients and four controls (365,708 nuclei) with subcellular spatial transcriptomics. We identified nerve cell type markers and uncovered unexpected heterogeneity of perineurial cells. PNPs shared a loss of myelinating and an increase in repair Schwann cells and endoneurial lipid-phagocytizing Macrophages. Transcriptional changes affected multiple cells outside of the endoneurium across PNPs, suggesting PNPs as 'pan-nerve diseases'. Spatially, PNPs-particularly those mediated by autoimmunity-exhibited focal perineurial hyperplasia and increased expression of CXCL14, identified as perineurial cell marker. Multi-omic characterization of human nerve biopsies thus identified novel mechanisms in PNPs with diagnostic potential.