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Cited by 128Neuroinflammation and Neurodegeneration MechanismsAmyotrophic Lateral Sclerosis ResearchSpinal Cord Injury Research

A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models

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Tyzack, Giulia E., Hall, Claire E., Sibley, Christopher R., Cymes, Tomasz, Forostyak, Serhiy, Carlino, Giulia, Meyer, Ione F., Schiavo, Giampietro +5 more·2017·Nature Communications
DOI 10.1038/s41467-017-01283-zPMC PMC5660125
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Abstract

Astrocyte responses to neuronal injury may be beneficial or detrimental to neuronal recovery, but the mechanisms that determine these different responses are poorly understood. Here we show that ephrin type-B receptor 1 (EphB1) is upregulated in injured motor neurons, which in turn can activate astrocytes through ephrin-B1-mediated stimulation of signal transducer and activator of transcription-3 (STAT3). Transcriptional analysis shows that EphB1 induces a protective and anti-inflammatory signature in astrocytes, partially linked to the STAT3 network. This is distinct from the response evoked by interleukin (IL)-6 that is known to induce both pro inflammatory and anti-inflammatory processes. Finally, we demonstrate that the EphB1–ephrin-B1 pathway is disrupted in human stem cell derived astrocyte and mouse models of amyotrophic lateral sclerosis (ALS). Our work identifies an early neuronal help-me signal that activates a neuroprotective astrocytic response, which fails in ALS, and therefore represents an attractive therapeutic target.

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  • hiPSC-derived astrocytes are rapidly becoming commonplace in basic research and therapy development.

    “are rapidly becoming commonplace in basic research11,82 and therapy development109”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [82]

    The Methods describe experiments with hiPSC-derived astrocytes, and the Discussion says human iPSC models can help identify astrocytic targets for potential treatment. This supports their relevance to therapy development, but the paper does not establish that their use is rapidly becoming commonplace. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The outcome of activating a signaling pathway may depend on the upstream stimuli or priming caused by previous exposure to other stimuli, perhaps through epigenetic control.

    “To complicate things further, the outcome of activating a signaling pathway may depend on the upstream stimuli82 or priming caused by previous exposure to other stimuli97, perhaps through epigenetic control40.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [82]

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Authors
Tyzack, G. E., Hall, C. E., Sibley, C. R., Cymes, T., Forostyak, S., Carlino, G., Meyer, I. F., Schiavo, G., Zhang, S.-C., Gibbons, G. M., Newcombe, J., Patani, R., & Lakatos, A.
Affiliations
  • University of Cambridge (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Imperial College London (GB)
  • Charles University (CZ)
  • UK Dementia Research Institute (GB)
  • University of Wisconsin System (US)
  • The Francis Crick Institute (GB)
Corresponding author
  • Patani, Rickie
  • Lakatos, András
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-10-27
Volume
8
Issue
1
Pages
1164-1164
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-01283-z
PMC
PMC5660125
OpenAlex
W2767003231
Cited by
128
References
10
Citations by year
2026: 4 · 2025: 9 · 2024: 13 · 2023: 21 · 2022: 17 · 2021: 21 · 2020: 16 · 2019: 18 · 2018: 8 · 2017: 1
FWCI
5.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • ASEP (submittedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Eli Lilly and Company
  • Wellcome Trust (101149/Z/13/Z, 101149, 101149/Z/13/A)
  • National Institute for Health and Care Research
  • University College London
  • Grantová Agentura České Republiky (GA17-21146S)
  • Dementias Platform UK
  • Medical Research Council (MR/M02492X/1, MR/P008658/1)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
Keywords
EphB1, ephrin-B1, astrocytes, neuroprotection, amyotrophic lateral sclerosis, motor neuron injury, STAT3 signaling, astrocyte activation, neuroinflammation, interleukin-6, therapeutic target
MeSH terms
Neuroprotection, Amyotrophic Lateral Sclerosis, Animals, Anti-Inflammatory Agents, Astrocytes, Axons, Cells, Cultured, Disease Models, Animal, Humans, Inflammation, Male, Mice, Inbred C57BL, Motor Neurons, Neurons, Sciatic Nerve, Signal Transduction, Interleukin-6, Receptor, EphB1, STAT3 Transcription Factor, Mice, Transcriptome

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