Human 3D cellular model of hypoxic brain injury of prematurity.

Abstract

Due to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes due to lung immaturity, hypotension, and lack of cerebral flow regulation, and can develop a severe condition called encephalopathy of prematurity (EP)3. Over 80% of infants born before post conception week (PCW) 25 have moderate to severe long-term neurodevelopmental impairments4. 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 show that these are related to the unfolded protein response (UPR) and cell cycle changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small molecule modulator of the UPR pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying environmental and genetic factors underlying brain injury in premature infants.