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

Michael Heming; Anna Lena Börsch; Jolien Wolbert; Christian Thomas; Anne K. Mausberg; Fabian Szepanowski; Bianca Eggert; I. Na Lu; Julia Tietz; Finja Dienhart; Maja Meschnark; Jan Kolja Strecker; Michael Glatza; Carolina Thomas; Noemi Gmahl; Christine Dambietz; Michael Müther; Anne Kathrin Uerschels; Kathy Keyvani; Jens Minnerup; Kathrin Doppler; Nurcan Üçeyler; Julieta Aprea; Andreas Dahl; Ruth Stassart; Robert Fledrich; Heinz Wiendl; Claudia Sommer; Mark Stettner; Gerd Meyer zu Hörste

doi:10.1038/s41467-025-62964-8

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

Michael Heming, Anna Lena Börsch, Jolien Wolbert, Christian Thomas, Anne K. Mausberg, Fabian Szepanowski, Bianca Eggert, I. Na Lu, Julia Tietz, Finja Dienhart, Maja Meschnark, Jan Kolja Strecker, Michael Glatza, Carolina Thomas, Noemi Gmahl, Christine Dambietz, Michael Müther, Anne Kathrin Uerschels, Kathy Keyvani, Jens MinnerupKathrin Doppler, Nurcan Üçeyler, Julieta Aprea, Andreas Dahl, Ruth Stassart, Robert Fledrich, Heinz Wiendl, Claudia Sommer, Mark Stettner, Gerd Meyer zu Hörste^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Klinik für Neurologie

3 Zitate (Scopus)

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.

Originalsprache	Englisch
Aufsatznummer	7872
Zeitschrift	Nature Communications
Jahrgang	16
Ausgabenummer	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-025-62964-8
Publikationsstatus	Veröffentlicht - 12.2025

Fördermittel

We are deeply indebted to the patients for their participation. We thank Rebecca Ley from the Institute of Neuropathology Münster, Birgit Schmeddes and Sophie Linnenbaum from the Department of Neurology Münster, Susanne Weiche from the Dresden-concept Genome Center, and Kristina Wagner from the Department of Neurology in Essen for technical assistance. This work was supported by the Core EM and Histology, a core facility of the CMCB Technology Platform at the Technische Universität Dresden. Part of the calculations were performed on the high-performance computing (HPC) cluster PALMA II of the University of Münster, subsidized by the DFG (INST 211/667-1). This project was supported by the National Competence Network for Immune-Mediated Neuropathies in Germany (Kompetenznetz Peripherer Nerv). This project was mainly funded by a grant from the Bundesministerium für Bildung und Forschung (BMBF) ‘Lipid Immune Neuropathy Consortium’ (to G.M.z.H., M.S., R.S., R.F.) and a grant from the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Münster (SEED/016/21 to M.H.). In addition, GMzH was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (ME4050/12-1, ME4050/13-1, ME4050/8-1). This project was also supported by the DFG Sonderforschungsbereich Transregio 128 (to H.W.). J.A. was supported by the DFG Research Infrastructure NGS_CC (INST 269/768, project 407482635, DRESDEN-concept Genome Center). Open Access funding enabled and organized by Projekt DEAL.

Träger	Trägernummer
Bundesministerium für Bildung und Forschung
Technische Universität Dresden
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg	SEED/016/21
Deutsche Forschungsgemeinschaft	ME4050/8-1, ME4050/12-1, ME4050/13-1, INST 269/768, 407482635

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SDG 3 – Gesundheit und Wohlergehen

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2.23-07 Klinische Neurologie, Neurochirurgie und Neuroradiologie

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10.1038/s41467-025-62964-8

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Heming, M., Börsch, A. L., Wolbert, J., Thomas, C., Mausberg, A. K., Szepanowski, F., Eggert, B., Lu, I. N., Tietz, J., Dienhart, F., Meschnark, M., Strecker, J. K., Glatza, M., Thomas, C., Gmahl, N., Dambietz, C., Müther, M., Uerschels, A. K., Keyvani, K., ... Meyer zu Hörste, G. (2025). Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies. Nature Communications, 16(1), Artikel 7872. https://doi.org/10.1038/s41467-025-62964-8

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title = "Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies",

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 {\textquoteleft}pan-nerve diseases{\textquoteright}. 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.",

author = "Michael Heming and B{\"o}rsch, \{Anna Lena\} and Jolien Wolbert and Christian Thomas and Mausberg, \{Anne K.\} and Fabian Szepanowski and Bianca Eggert and Lu, \{I. Na\} and Julia Tietz and Finja Dienhart and Maja Meschnark and Strecker, \{Jan Kolja\} and Michael Glatza and Carolina Thomas and Noemi Gmahl and Christine Dambietz and Michael M{\"u}ther and Uerschels, \{Anne Kathrin\} and Kathy Keyvani and Jens Minnerup and Kathrin Doppler and Nurcan {\"U}{\c c}eyler and Julieta Aprea and Andreas Dahl and Ruth Stassart and Robert Fledrich and Heinz Wiendl and Claudia Sommer and Mark Stettner and \{Meyer zu H{\"o}rste\}, Gerd",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-62964-8",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "1751-8628",

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Heming, M, Börsch, AL, Wolbert, J, Thomas, C, Mausberg, AK, Szepanowski, F, Eggert, B, Lu, IN, Tietz, J, Dienhart, F, Meschnark, M, Strecker, JK, Glatza, M, Thomas, C, Gmahl, N, Dambietz, C, Müther, M, Uerschels, AK, Keyvani, K, Minnerup, J, Doppler, K, Üçeyler, N, Aprea, J, Dahl, A, Stassart, R, Fledrich, R, Wiendl, H, Sommer, C, Stettner, M & Meyer zu Hörste, G 2025, 'Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies', Nature Communications, Jg. 16, Nr. 1, 7872. https://doi.org/10.1038/s41467-025-62964-8

TY - JOUR

T1 - Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies

AU - Heming, Michael

AU - Börsch, Anna Lena

AU - Wolbert, Jolien

AU - Thomas, Christian

AU - Mausberg, Anne K.

AU - Szepanowski, Fabian

AU - Eggert, Bianca

AU - Lu, I. Na

AU - Tietz, Julia

AU - Dienhart, Finja

AU - Meschnark, Maja

AU - Strecker, Jan Kolja

AU - Glatza, Michael

AU - Thomas, Carolina

AU - Gmahl, Noemi

AU - Dambietz, Christine

AU - Müther, Michael

AU - Uerschels, Anne Kathrin

AU - Keyvani, Kathy

AU - Minnerup, Jens

AU - Doppler, Kathrin

AU - Üçeyler, Nurcan

AU - Aprea, Julieta

AU - Dahl, Andreas

AU - Stassart, Ruth

AU - Fledrich, Robert

AU - Wiendl, Heinz

AU - Sommer, Claudia

AU - Stettner, Mark

AU - Meyer zu Hörste, Gerd

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105013875628

U2 - 10.1038/s41467-025-62964-8

DO - 10.1038/s41467-025-62964-8

M3 - Journal articles

C2 - 40849297

AN - SCOPUS:105013875628

SN - 1751-8628

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7872

ER -

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

Abstract

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