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Cited by 45Neonatal and fetal brain pathologyNeurogenesis and neuroplasticity mechanismsFetal and Pediatric Neurological Disorders

Minocycline mitigates the effect of neonatal hypoxic insult on human brain organoids

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Boisvert, Erin M., Means, Robert E., Michaud, Michael, Madri, Joseph A., Katz, Samuel G.·2019·Cell Death & Disease
DOI 10.1038/s41419-019-1553-xPMC PMC6459920
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Abstract

Neonatal hypoxic injury (NHI) is a devastating cause of disease that affects >60% of babies born with a very low birth weight, resulting in significant morbidity and mortality, including life-long neurological consequences such as seizures, cerebral palsy, and intellectual disability. Hypoxic injury results in increased neuronal death, which disrupts normal brain development. Although animal model systems have been useful to study the effects of NHI, they do not fully represent the uniqueness and complexities of the human brain. To better understand the effects of hypoxia on human brain development, we have generated a brain organoid protocol and evaluated these cells over the course of 6 months. As anticipated, the expression of a forebrain marker, FOXG1, increased and then remained expressed over time, while there was a transition in the expression of the deep-layer (TBR1) and upper-layer (SATB2) cortical markers. In addition, ventral genes (Eng1 and Nkx2.1) as well as markers of specialized nonneuronal cells (Olig2 and GFAP) also increased at later time points. We next tested the development of our in vitro cerebral organoid model at different oxygen concentrations and found that hypoxia repressed gene markers for forebrain, oligodendrocytes, glial cells, and cortical layers, as well as genes important for the migration of cortical neurons. In contrast, ventral markers were either unaffected or even increased in expression with hypoxic insult. Interestingly, the negative effect of hypoxia on the dorsal brain genes as well as oligodendrocytes, and neuronal progenitors could be mitigated by the use of minocycline, an FDA-approved small molecule. Taken together, we have generated a unique and relevant in vitro human brain model system to study diseases such as NHI as well as their potential treatments. Using this system, we have shown the efficacy of minocycline for human NHI.

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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 [30]

    The Discussion (page unavailable) reports substantial batch-to-batch variability in several brain organoid systems and identifies necrosis as a potential concern in existing models. It does not specify variation in size and composition or discuss physical damage from microglia injection. The authors also report no apparent necrosis in their own organoids for up to 5–6 months. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Boisvert, E. M., Means, R. E., Michaud, M., Madri, J. A., & Katz, S. G.
Affiliations
Yale University (US)
Corresponding author
Katz, Samuel G.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-04-11
Volume
10
Issue
4
Pages
325-325
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-1553-x
PMC
PMC6459920
OpenAlex
W2938338045
Cited by
45
References
6
Citations by year
2026: 5 · 2025: 9 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 2
FWCI
5.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Connecticut Innovations (Regenerative Medicine Research Fund)
  • March of Dimes Foundation
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL131793)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA193200)
  • Gift from Joseph and Lucille Madri.
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
Keywords
minocycline, human brain organoids, hypoxia, brain development, FOXG1, Tbr1, SATB2, TTF-1, Olig2, glial fibrillary acidic protein, oligodendrocyte development, neuronal migration, oxygen concentration, very low birth weight, neuroprotection
MeSH terms
Human Embryonic Stem Cells, Brain, Hypoxia, Brain, Humans, Minocycline, Neurons, Organoids, Time Factors, Cell Death, Proto-Oncogene Proteins c-bcl-2, Hypoxia-Ischemia, Brain, SOXB1 Transcription Factors

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