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Cited by 120Amyotrophic Lateral Sclerosis ResearchMultiple Sclerosis Research StudiesSingle-cell and spatial transcriptomics

Altered perivascular fibroblast activity precedes ALS disease onset

Open access
Månberg, Anna, Skene, Nathan, Sanders, Folkert, Trusohamn, Marta, Remnestål, Julia, Szczepińska, Anna, Aksoylu, Inci Sevval, Lönnerberg, Peter +26 more·2021·Nature Medicine
DOI 10.1038/s41591-021-01295-9PMC PMC7613336
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Abstract

Apart from well-defined factors in neuronal cells 1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia 2,3 and blood vessels 4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.

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Authors
Månberg, A., Skene, N., Sanders, F., Trusohamn, M., Remnestål, J., Szczepińska, A., Aksoylu, I. S., Lönnerberg, P., Ebarasi, L., Wouters, S., Lehmann, M., Olofsson, J., von Gohren Antequera, I., Domaniku, A., De Schaepdryver, M., De Vocht, J., Poesen, K., Uhlén, M., Anink, J., Mijnsbergen, C., Vergunst-Bosch, H., Hübers, A., Kläppe, U., Rodriguez-Vieitez, E., Gilthorpe, J. D., Hedlund, E., Harris, R. A., Aronica, E., Van Damme, P., Ludolph, A., Veldink, J., Ingre, C., Nilsson, P., & Lewandowski, S. A.
Affiliations
  • Science for Life Laboratory (SE)
  • Karolinska Institutet (SE)
  • Karolinska University Hospital (SE)
  • Umeå University (SE)
  • Universitair Ziekenhuis Leuven (BE)
  • Amsterdam Neuroscience (NL)
  • Utrecht University (NL)
  • Universität Ulm (DE)
Corresponding author
Lewandowski, Sebastian A.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-04
Volume
27
Issue
4
Pages
640-646
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-021-01295-9
PMC
PMC7613336
OpenAlex
W3152771199
Cited by
120
References
74
Citations by year
2026: 17 · 2025: 21 · 2024: 15 · 2023: 24 · 2022: 35 · 2021: 7
FWCI
9.57
Type
journal article
Language
en
Update notices
correction (2021-06-02)
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion)
Funders
Wellcome Trust (108726, 108726/Z/15/Z)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
amyotrophic lateral sclerosis, perivascular fibroblasts, vascular remodeling, presymptomatic disease, osteopontin, COL6A1, survival prediction, plasma biomarkers, spinal cord gene expression, microglial activation, ALS etiology
MeSH terms
Amyotrophic Lateral Sclerosis, Animals, Blood Vessels, DNA-Binding Proteins, Fibroblasts, Genetic Markers, Humans, Mice, Transgenic, Prognosis, RNA, Messenger, Spinal Cord, Superoxide Dismutase, Transcription, Genetic, Biomarkers, Disease Progression, Collagen Type VI, Osteopontin, Vascular Remodeling

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