Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

  1. Lindsay A Hohsfield
  2. Allison R Najafi
  3. Yasamine Ghorbanian
  4. Neelakshi Soni
  5. Joshua Crapser
  6. Dario X Figueroa Velez
  7. Shan Jiang
  8. Sarah E Royer
  9. Sung Jin Kim
  10. Caden M Henningfield
  11. Aileen Anderson
  12. Sunil P Gandhi
  13. Ali Mortazavi
  14. Matthew A Inlay
  15. Kim N Green  Is a corresponding author
  1. University of California, Irvine, United States
  2. University of Connecticut Health Center, United States
  3. University of California Irvine, United States
  4. UC Irvine, United States

Abstract

Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangentially in a dynamic wave filling the brain in a distinct pattern, to replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit similar phenotypic and transcriptional profiles to white matter-associated microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into repopulating microglia function and dynamics in the mouse brain.

Data availability

Sequencing data have been deposited in GEO under accession code GSE166092, and can be explored in an interactive fashion at http://rnaseq.mind.uci.edu/green/. All other data generated or analysed during this study are included in the manuscript and support files.

The following data sets were generated

Article and author information

Author details

  1. Lindsay A Hohsfield

    Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Allison R Najafi

    Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yasamine Ghorbanian

    Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Neelakshi Soni

    Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joshua Crapser

    Neuroscience, University of Connecticut Health Center, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dario X Figueroa Velez

    Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Shan Jiang

    Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sarah E Royer

    Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sung Jin Kim

    Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Caden M Henningfield

    Anatomy and Neurobiology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Aileen Anderson

    Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8203-8891
  12. Sunil P Gandhi

    Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Ali Mortazavi

    Developmental and Cell Biology, University of California Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Matthew A Inlay

    Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Kim N Green

    Neurobiology & Behavior, UC Irvine, Irvine, United States
    For correspondence
    kngreen@uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6049-6744

Funding

National Institute of Neurological Disorders and Stroke (R01NS083801)

  • Kim N Green

National Institute on Aging (R01AG056768)

  • Kim N Green

National Institute on Aging (P50AG016573)

  • Kim N Green

National Institute of Neurological Disorders and Stroke (F31NS108611)

  • Joshua Crapser

National Institute of Neurological Disorders and Stroke (T32NS082174)

  • Yasamine Ghorbanian

Alzheimer's Association (AARF-16-442762)

  • Lindsay A Hohsfield

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 rodent experiments were performed in accordance with animal protocols approved (AUP-17-179) by the Institutional Animal Care and Use Committee at the University of California, Irvine (UCI).

Reviewing Editor

  1. Jaime Grutzendler, Yale University, United States

Publication history

  1. Received: January 20, 2021
  2. Preprint posted: February 18, 2021 (view preprint)
  3. Accepted: August 22, 2021
  4. Accepted Manuscript published: August 23, 2021 (version 1)
  5. Version of Record published: September 8, 2021 (version 2)

Copyright

© 2021, Hohsfield 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. Lindsay A Hohsfield
  2. Allison R Najafi
  3. Yasamine Ghorbanian
  4. Neelakshi Soni
  5. Joshua Crapser
  6. Dario X Figueroa Velez
  7. Shan Jiang
  8. Sarah E Royer
  9. Sung Jin Kim
  10. Caden M Henningfield
  11. Aileen Anderson
  12. Sunil P Gandhi
  13. Ali Mortazavi
  14. Matthew A Inlay
  15. Kim N Green
(2021)
Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave
eLife 10:e66738.
https://doi.org/10.7554/eLife.66738

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