Microfluidic intestinal organoid-on-a-chip uncovers therapeutic targets by recapitulating oxygen dynamics of intestinal IR injury

类有机物 缺氧(环境) 细胞生物学 化学 纤毛 肠粘膜 细胞 氧气 生物物理学 生物 生物化学 医学 内科学 有机化学
作者
Jinjian Huang,Ziyan Xu,Jiao Jiao,Zongan Li,Sicheng Li,Ye Liu,Ze Li,Guiwen Qu,Jie Wu,Yun Zhao,Kang Chen,Jieshou Li,Yichang Pan,Xiuwen Wu,Jianan Ren
出处
期刊:Bioactive Materials [Elsevier]
卷期号:30: 1-14 被引量:1
标识
DOI:10.1016/j.bioactmat.2023.07.001
摘要

Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24 h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury.
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