Challenges to, and prospects for, reverse engineering the gastrointestinal tract using organoids

Kakni, Panagiota; Truckenmüller, Roman; Habibović, Pamela; Giselbrecht, Stefan

doi:10.1016/j.tibtech.2022.01.006

Cited by 15 publications

(16 citation statements)

References 94 publications

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“…Intestinal organoids are self-organizing, three-dimensional (3D) mini-organs that can be derived from stem cells and recapitulate multiple features of the in vivo intestine [ 9 , 10 ]. Specifically, they have a multicellular composition, they are organized into crypt-villus structures, and they are able to perform intestine-specific functions such as barrier formation and nutrient uptake [ 11 ]. Organoids recapitulate intestinal properties much closer than 2D monolayer systems (e.g., using Caco-2 cells) and allow for in-depth analysis of pathogen–host interactions and investigation of mechanisms related to development and disease.…”

Section: Introductionmentioning

confidence: 99%

A Microwell-Based Intestinal Organoid-Macrophage Co-Culture System to Study Intestinal Inflammation

Kakni

Truckenmüller

Habibović

et al. 2022

IJMS

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The mammalian intestinal epithelium contains more immune cells than any other tissue, and this is largely because of its constant exposure to pathogens. Macrophages are crucial for maintaining intestinal homeostasis, but they also play a central role in chronic pathologies of the digestive system. We developed a versatile microwell-based intestinal organoid-macrophage co-culture system that enables us to recapitulate features of intestinal inflammation. This microwell-based platform facilitates the controlled positioning of cells in different configurations, continuous in situ monitoring of cell interactions, and high-throughput downstream applications. Using this novel system, we compared the inflammatory response when intestinal organoids were co-cultured with macrophages versus when intestinal organoids were treated with the pro-inflammatory cytokine TNF-α. Furthermore, we demonstrated that the tissue-specific response differs according to the physical distance between the organoids and the macrophages and that the intestinal organoids show an immunomodulatory competence. Our novel microwell-based intestinal organoid model incorporating acellular and cellular components of the immune system can pave the way to unravel unknown mechanisms related to intestinal homeostasis and disorders.

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Section: Introductionmentioning

confidence: 99%

A Microwell-Based Intestinal Organoid-Macrophage Co-Culture System to Study Intestinal Inflammation

Kakni

Truckenmüller

Habibović

et al. 2022

IJMS

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“… 1 , 7 Based on their proven capacity to closely resemble the intestinal epithelium, organoids have been used for the study of intestinal microbiota-host interactions. 8 – 10 Specifically, organoids have been co-cultured with commensal bacteria, such as Lactobacillus 11 – 13 and non-pathogenic Escherichia coli (E. coli) strains, 14 and pathogenic bacteria, such as Cryptosporidium , 15 Salmonella enterica serovar Typhimurium, 16 , 17 E. coli strains, 17 – 22 Clostridioides difficile , 23 – 25 and Bacteroides thetaiotaomicron . 26 In these systems, to bring the microorganisms in contact with the apical surface of the epithelial cells of the organoids, microinjenctions of the bacteria into the central lumen were necessary.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-tolerant apical-out intestinal organoids to model host-microbiome interactions

et al. 2023

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Microbiome is an integral part of the gut and is essential for its proper function. Imbalances of the microbiota can be devastating and have been linked with several gastrointestinal conditions. Current gastrointestinal models do not fully reflect the in vivo situation. Thus, it is important to establish more advanced in vitro models to study host-microbiome/pathogen interactions. Here, we developed for the first time an apical-out human small intestinal organoid model in hypoxia, where the apical surface is directly accessible and exposed to a hypoxic environment. These organoids mimic the intestinal cell composition, structure and functions and provide easy access to the apical surface. Co-cultures with the anaerobic strains Lactobacillus casei and Bifidobacterium longum showed successful colonization and probiotic benefits on the organoids. These novel hypoxia-tolerant apical-out small intestinal organoids will pave the way for unraveling unknown mechanisms related to host-microbiome interactions and serve as a tool to develop microbiome-related probiotics and therapeutics.

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“…of the in vivo intestine ( Sato et al, 2009 ; Spence et al, 2011 ), organize into crypt-villus structures and possess tissue polarity, thus mimicking the architecture and function of the intestinal epithelium. Intestinal organoids have been utilized in numerous studies related to nutrient transport, metabolism and drug development ( Zietek et al, 2015 ; Zietek et al, 2020 ; Negoro et al, 2018 ; Onozato et al, 2018 ; Janssen et al, 2020 ; Kasendra et al, 2020 ) and thus hold a great promise as a tool to study intestinal development, physiology and disorders ( Günther et al, 2019 ; Kakni et al, 2022b ). Pluripotent stem cells (PSC) have shown a remarkable ability to differentiate towards all the cell types of the body and they can be used as a source for generating intestinal organoids ( Spence et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

PSC-derived intestinal organoids with apical-out orientation as a tool to study nutrient uptake, drug absorption and metabolism

Kakni

López‐Iglesias

Truckenmüller

et al. 2023

Front. Mol. Biosci.

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Intestinal organoids recapitulate many features of the in vivo gastrointestinal tract and have revolutionized in vitro studies of intestinal function and disease. However, the restricted accessibility of the apical surface of the organoids facing the central lumen (apical-in) limits studies related to nutrient uptake and drug absorption and metabolism. Here, we demonstrate that pluripotent stem cell (PSC)-derived intestinal organoids with reversed epithelial polarity (apical-out) can successfully recapitulate tissue-specific functions. In particular, these apical-out organoids show strong epithelial barrier formation with all the major junctional complexes, nutrient transport and active lipid metabolism. Furthermore, the organoids express drug-metabolizing enzymes and relevant apical and basolateral transporters. The scalable and robust generation of functional, apical-out intestinal organoids lays the foundation for a completely new range of organoid-based high-throughput/high-content in vitro applications in the fields of nutrition, metabolism and drug discovery.

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Challenges to, and prospects for, reverse engineering the gastrointestinal tract using organoids

Cited by 15 publications

References 94 publications

A Microwell-Based Intestinal Organoid-Macrophage Co-Culture System to Study Intestinal Inflammation

A Microwell-Based Intestinal Organoid-Macrophage Co-Culture System to Study Intestinal Inflammation

Hypoxia-tolerant apical-out intestinal organoids to model host-microbiome interactions

PSC-derived intestinal organoids with apical-out orientation as a tool to study nutrient uptake, drug absorption and metabolism

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