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^*

^*Corresponding author for this work

Department of Neurology

3 Citations (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.

Original language	English
Article number	7872
Journal	Nature Communications
Volume	16
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-025-62964-8
Publication status	Published - 12.2025

Funding

Funders	Funder number
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

DFG Research Classification Scheme

2.23-07 Clinical Neurology, Neurosurgery and Neuroradiology

Access to Document

10.1038/s41467-025-62964-8

Cite this

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), Article 7872. https://doi.org/10.1038/s41467-025-62964-8

@article{0022ecc261dd462ba81ffa360d18564c,

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",

publisher = "John Wiley \& Sons Inc.",

number = "1",

}

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, vol. 16, no. 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

Funding

UN SDGs

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

Cite this