1. Neuroscience
  2. Stem Cells and Regenerative Medicine
Download icon

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
Research Article
  • Cited 1
  • Views 2,939
  • Annotations
Cite this article as: eLife 2020;9:e59733 doi: 10.7554/eLife.59733

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.

Metrics

  • 2,939
    Page views
  • 414
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

  1. Listen to Jens Magnusson explain how astrocytes are able to form new neurons.

    Podcast

    Supporting cells in the brain are able to form new neurons in response to injury

    1. Neuroscience

    Neural signatures of vigilance decrements predict behavioural errors before they occur

    Hamid Karimi-Rouzbahani et al.
    Research Article Updated

    There are many monitoring environments, such as railway control, in which lapses of attention can have tragic consequences. Problematically, sustained monitoring for rare targets is difficult, with more misses and longer reaction times over time. What changes in the brain underpin these ‘vigilance decrements’? We designed a multiple-object monitoring (MOM) paradigm to examine how the neural representation of information varied with target frequency and time performing the task. Behavioural performance decreased over time for the rare target (monitoring) condition, but not for a frequent target (active) condition. This was mirrored in neural decoding using magnetoencephalography: coding of critical information declined more during monitoring versus active conditions along the experiment. We developed new analyses that can predict behavioural errors from the neural data more than a second before they occurred. This facilitates pre-empting behavioural errors due to lapses in attention and provides new insight into the neural correlates of vigilance decrements.

    1. Medicine
    2. Neuroscience

    Respiratory depression and analgesia by opioid drugs in freely behaving larval zebrafish

    Shenhab Zaig et al.
    Research Article Updated

    An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by μ-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.