The Affilated Hospital, Southwest Medical University, Sichuan, China
Abstract: Fetal hypoxia impacts development and causes 23% of neonatal deaths. The prenatal brain is highly susceptible to hypoxic exposure. Nevertheless, the specific cell types affected and the underlying molecular mechanisms that mediate hypoxic brain injury remain incompletely understood. To address this issue, we developed brain organoids modelling human fetal brain hypoxic injury during the early to mid-gestational period. Utilizing single-cell transcriptome analysis, we identified seven distinct cell types within these brain organoids, representing major cortical progenitors and neurons present in the fetal brain at this developmental stage. Specifically, we observed distinct alterations in mTORC1 signaling, fatty acid synthesis, unfolded protein response, and innate immune responses among these cell types under hypoxic conditions. Notably, unlike cortical progenitors, developing glutamatergic and GABAergic neurons exhibited a pronounced delay in maturation following hypoxic exposure. Furthermore, our analysis identified two distinct GABAergic neuron subtypes that displayed differential sensitivities to hypoxia: type 2 neurons, which are more mature, were found to be more susceptible to hypoxia-induced neural functional impairments compared to type 1 neurons. In summary, our study provides a comprehensive understanding of the distinct cellular responses among cortical progenitors and neurons in fetal hypoxic brain injury, offering potential therapeutic targets for this condition.
Funding Source: This work was supported by grants from the National Natural Science Foundation of China (32300675, 32400598), Sichuan Science and Technology Program (2022YFS0615, 2025ZNSFSC1019)
