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Cited by 624Neurogenesis and neuroplasticity mechanismsSingle-cell and spatial transcriptomicsDevelopmental Biology and Gene Regulation

Cell stress in cortical organoids impairs molecular subtype specification

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Bhaduri, Aparna, Andrews, Madeline G., Mancia Leon, Walter, Jung, Diane, Shin, David, Allen, Denise, Jung, Dana, Schmunk, Galina +5 more·2020·Nature
DOI 10.1038/s41586-020-1962-0PMC PMC7433012
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Abstract

Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex 1,2. However, the fidelity of organoid models remains unclear 3-5. Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.

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  • These microglia/organoid models still suffer from variation of organoid size and composition, confounds stemming from organoid hypoxia/necrosis, and physical damage from microglia injection.

    “However, these microglia/organoid models still suffer from (1) variation of organoid size and composition; (2) confounds stemming from organoid hypoxia/necrosis; and (3) physical damage from microglia injection.29–31”

    From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [29]

    The sections “Cellular Stress Increases in Organoids” and “Organoid Environment Activates Stress” report stress in organoid cells, supporting a general concern about culture-related confounds. They do not establish hypoxia or necrosis as the cause. “Impaired Cell Type Fidelity in Organoids” says composition was similar across organoids of the same age, and the paper does not report organoid-size variation or damage from injecting microglia; its injection methods concern transplanting organoid cells into mice. (LLM, conf=0.82)

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Authors
Bhaduri, A., Andrews, M. G., Mancia Leon, W., Jung, D., Shin, D., Allen, D., Jung, D., Schmunk, G., Haeussler, M., Salma, J., Pollen, A. A., Nowakowski, T. J., & Kriegstein, A. R.
Affiliations
  • University of California, San Francisco (US)
  • University of California, Santa Cruz (US)
  • Aga Khan University (PK)
Corresponding author
Kriegstein, Arnold R.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-01-29
Volume
578
Issue
7793
Pages
142-148
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-1962-0
PMC
PMC7433012
OpenAlex
W3004345103
Cited by
624
References
15
Citations by year
2026: 82 · 2025: 82 · 2024: 101 · 2023: 91 · 2022: 106 · 2021: 85 · 2020: 75 · 2012: 1
FWCI
35.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eCommons - AKU (Aga Khan University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Medical Research Council (MR/R006237/1)
  • National Institute of Mental Health (U01MH114825, F32MH118785)
  • National Institute of Neurological Disorders and Stroke (F32NS103266, R35NS097305, K99NS111731)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
cortical organoids, cortical development, cellular stress, neuronal subtype specification, single-cell transcriptomics, organoid transplantation, transcriptome
MeSH terms
Cerebral Cortex, Humans, Neurons, Organoids, Stress, Physiological, Tissue Culture Techniques, Neurogenesis, Single-Cell Analysis

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