Yang Li1 · Xin‑Yao Sun1,2 · Peng‑Ming Zeng1 · Zhen‑Ge Luo11 School of Life Science and Technology & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
2 Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
Abstract
Hypoxic injury (HI) in the prenatal period often causes neonatal neurological disabilities. Due to the difficulty in obtaining clinical samples, the molecular and cellular mechanisms remain unclear. Here we use vascularized cerebral organoids to investigate the hypoxic injury phenotype and explore the intercellular interactions between vascular and neural tissues under hypoxic conditions. Our results indicate that fused vascularized cerebral organoids exhibit broader hypoxic responses and larger decreases in panels of neural development-related genes when exposed to low oxygen levels compared to single cerebral organoids. Interestingly, vessels also exhibit neural protective effects on T-box brain protein 2+ intermediate progenitors (IPs), which are markedly lost in HI cerebral organoids. Furthermore, we identify the role of bone morphogenic protein signaling in protecting IPs. Thus, this study has established an in vitro organoid system that can be used to study the contribution of vessels to brain injury under hypoxic conditions and provides a strategy for the identification of intervention targets.
Keywords
Hypoxia; Hypoxic-injury encephalopathy; Cerebral organoid; Vascularized cerebral organoid; BMP signaling
