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 ultr...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 coaxial 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 downregulated 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 multisysteminteractive organoid chip for finding precise therapeutic targets of IR injury.展开更多
基金the National Natural Science Foundation of China(82270595,82272237,82072223,32171402)the China Postdoctoral Science Foundation(BX20220393,2022M723891)+2 种基金the General Program of Medical Research from the Jiangsu Commission of Health(M2020052)the Jiangsu Key Research and Development Plan(BE2021727)Jiangsu Provincial Medical Innovation Center(CXZX202217).
文摘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 coaxial 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 downregulated 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 multisysteminteractive organoid chip for finding precise therapeutic targets of IR injury.
