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

ABSTRACT: 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.

SUBMITTER: Huang J

PROVIDER: S-EPMC10391666 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Huang Jinjian J Xu Ziyan Z Jiao Jiao J Li Zongan Z Li Sicheng S Liu Ye Y Li Ze Z Qu Guiwen G Wu Jie J Zhao Yun Y Chen Kang K Li Jieshou J Pan Yichang Y Wu Xiuwen X Ren Jianan J

Bioactive materials 20230721

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-responsiv ...[more]

PMID: 37534235

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Project description:Vascular interactions play a crucial role in embryogenesis, including skeletal development. During endochondral ossification, vascular networks are formed as mesenchymal cells condense and later invade skeletal elements to form the bone marrow. We and other groups developed a model of endochondral ossification by implanting human embryonic stem cell (hESC)-derived sclerotome into immunodeficient mice. However, in vitro models of endochondral ossification, particularly vascular interaction with mesenchymal cells at its initial stage, are yet to be established. Therefore, we developed a method to model the initial stage of endochondral ossification using a microfluidic chip-based platform, with a particular focus on the vascular interaction. On the chip, we found that the fibrin gel helped align mCherry-expressing human umbilical vein endothelial cells (HUVECs) better than the collagen-I gel, suggesting that the fibrin gel is more suitable for the formation of a vascular-like network. The perfusability of the vascular-like networks was partially confirmed using fluorescein isothiocyanate (FITC)-dextran and fluorescent microbeads. We then mixed hESC-derived sclerotome with enhanced green fluorescent protein (EGFP)-expressing HUVECs and applied this mixture on the chip. We named this mixture of cells SH organoids. The SH organoids showed superior abilities to maintain the vascular-like network, which was formed by the mCherry-expressing HUVECs, compared with the sclerotome spheroids on the chip. The EGFP-expressing HUVECs migrated from the SH organoid, formed a vascular-like networks, and partially interacted with the mCherry-expressing vascular-like networks on the chip. Histological analysis showed that SRY-box transcription factor 9 (SOX9) and type I collagen were expressed mutually exclusively in the condensed mesenchymal cells and perichondrial-like cells, respectively. This study demonstrates that our SH organoid-on-a-chip method reproduces vascular networks that are formed at the initial stage of endochondral ossification. This model may provide insights into human endochondral ossification and has potential applications in bone disease modeling and drug screening.

Dataset Information

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

Publications

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

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