Activation of a neural stem cell transcriptional program in parenchymal astrocytes

  1. Jens P Magnusson
  2. Margherita Zamboni
  3. Giuseppe Santopolo
  4. Jeff E Mold
  5. Mauricio Barrientos-Somarribas
  6. Carlos Talavera-Lopez
  7. Björn Andersson
  8. Jonas Frisén  Is a corresponding author
  1. Stanford University, United States
  2. Karolinska Institutet, Sweden
  3. Francis Crick Institute, United Kingdom
  4. Karolinska Institute, Sweden

Abstract

Adult neural stem cells, located in discrete brain regions, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells, progressing through a near-identical neurogenic program. Surprisingly, in the non-neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, these cortical astrocytes, and many striatal ones, stalled before entering transit-amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

Data availability

The Cx30-CreER dataset (fastq files and processed expression matrix) has been deposited in ArrayExpress (accession E-MTAB-9268). The AAV-Cre dataset has been deposited in the Gene Expression Omnibus (GEO; accession GSE153916).SmartSeq2 dataset (ArrayExpress)http://www.ebi.ac.uk/arrayexpress/help/how_to_search_private_data.htmlUsername: Reviewer_E-MTAB-9268Password: hqhgiiqx10X dataset (GEO)To review GEO accession GSE153916:Go to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153916Enter token mzoxeoigpranfub into the box

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jens P Magnusson

    Bioengineering Department, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3928-8959
  2. Margherita Zamboni

    Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Giuseppe Santopolo

    Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeff E Mold

    Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  5. Mauricio Barrientos-Somarribas

    Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  6. Carlos Talavera-Lopez

    Francis Crick Institute, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Björn Andersson

    Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  8. Jonas Frisén

    Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
    For correspondence
    jonas.frisen@ki.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5819-458X

Funding

Svenska Forskningsrådet Formas

  • Jonas Frisén

Cancerfonden

  • Jonas Frisén

Stiftelsen för Strategisk Forskning

  • Jonas Frisén

H2020 European Research Council

  • Jonas Frisén

Knut och Alice Wallenbergs Stiftelse

  • Jonas Frisén

Torsten Söderbergs Stiftelse

  • Jonas Frisén

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experimental procedures were approved by the Stockholms Norra Djurförsöksetiska Nämnd (Permit reference numbers N571-11 and N155-16)

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: June 5, 2020
  2. Accepted: July 31, 2020
  3. Accepted Manuscript published: August 3, 2020 (version 1)
  4. Version of Record published: August 20, 2020 (version 2)

Copyright

© 2020, Magnusson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jens P Magnusson
  2. Margherita Zamboni
  3. Giuseppe Santopolo
  4. Jeff E Mold
  5. Mauricio Barrientos-Somarribas
  6. Carlos Talavera-Lopez
  7. Björn Andersson
  8. Jonas Frisén
(2020)
Activation of a neural stem cell transcriptional program in parenchymal astrocytes
eLife 9:e59733.
https://doi.org/10.7554/eLife.59733

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