Journal Article

Human 3D cellular model of hypoxic brain injury of prematurity

Shin, Hyun-Woo, Pașca, Anca M., Qi, Qihao, Revah, Omer, Krasnoff, Rebecca, Park, Jin-Young, O’Hara, Ruth, Palmer, Theo D., Pașca, Sergiu P., Willsey, A. Jeremy

2019

Overview

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. Brain organoids derived from human iPSCs are used to study the effects of hypoxia on early cortical neurodevelopment and identify defects in specific human progenitor populations that likely contribute to encephalopathy of prematurity.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/1689 / 631/532/2182 / Anoxia / Biomedical and Life Sciences / Biomedicine / Brain / Brain cells / Brain injuries / Brain Injuries - etiology / Brain Injuries - metabolism / Brain Injuries - pathology / Brain injury / Cancer Research / Cell Hypoxia - genetics / Cell Hypoxia - physiology / Cerebral cortex / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Defects / Deprivation / Encephalopathy / Genetic factors / Head injuries / Health aspects / Humans / Hypotension / Hypoxia / Hypoxia, Brain - etiology / Hypoxia, Brain - metabolism / Hypoxia, Brain - pathology / Infant development / Infant, Extremely Premature / Infant, Newborn / Infants / Infectious Diseases / Letter / Lungs / Metabolic Diseases / Models, Neurological / Molecular Medicine / Molecular modelling / Neonates / Neural Stem Cells - metabolism / Neural Stem Cells - pathology / Neurodevelopment / Neurogenesis - genetics / Neurogenesis - physiology / Neurosciences / Newborn infants / Organoids / Organoids - metabolism / Organoids - pathology / Pediatric research / Premature infants / Protein folding / Proteins / Risk factors / Survival / T-Box Domain Proteins - metabolism / Three dimensional models / Unfolded Protein Response