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Cited by 174Neonatal and fetal brain pathologyNeurogenesis and neuroplasticity mechanismsFetal and Pediatric Neurological Disorders

Human 3D cellular model of hypoxic brain injury of prematurity

Open access
Pașca, Anca M., Park, Jin-Young, Shin, Hyun-Woo, Qi, Qihao, Revah, Omer, Krasnoff, Rebecca, O’Hara, Ruth, Willsey, A. Jeremy +2 more·2019·Nature Medicine
DOI 10.1038/s41591-019-0436-0PMC PMC7020938
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Abstract

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates 1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity 3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments 4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.

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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 [31]

    The study-limitations passage (section labeled Abstract; page unavailable) says this model does not include microglia and proposes incorporating them in future models. Our copy discusses experimentally induced hypoxia, but does not identify organoid hypoxia or necrosis as a confound of microglia/organoid models. Searches for size and composition variation and damage from microglia injection likewise found no supporting passage. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Authors
Pașca, A. M., Park, J.-Y., Shin, H.-W., Qi, Q., Revah, O., Krasnoff, R., O’Hara, R., Willsey, A. J., Palmer, T. D., & Pașca, S. P.
Affiliations
  • Stanford Medicine (US)
  • Stanford University (US)
  • Seoul National University (KR)
  • University of California, San Francisco (US)
Corresponding author
Pașca, Sergiu P.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-05
Volume
25
Issue
5
Pages
784-791
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-019-0436-0
PMC
PMC7020938
OpenAlex
W2942868704
Cited by
174
References
13
Citations by year
2026: 18 · 2025: 28 · 2024: 17 · 2023: 21 · 2022: 33 · 2021: 24 · 2020: 23 · 2019: 10
FWCI
23.40
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Mental Health (R01MH108660, R01MH108659, R01MH107800)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD000850)
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
encephalopathy of prematurity, hypoxic brain injury, preterm birth, brain organoids, cortical development, intermediate progenitor cells, unfolded protein response, oxygen deprivation, small molecule modulators, iPSC-derived neurons, neurodevelopmental impairment
MeSH terms
Brain Injuries, Hypoxia, Brain, Cerebral Cortex, Humans, Infant, Newborn, Models, Neurological, Organoids, Cell Hypoxia, T-Box Domain Proteins, Neurogenesis, Unfolded Protein Response, Neural Stem Cells, Infant, Extremely Premature

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