An iPSC-derived small intestine-on-chip with self-organizing epithelial, mesenchymal, and neural cells

Moerkens, Renée; Mooiweer, Joram; Ramírez-Sánchez, Aarón D.; Oelen, Roy; Franke, Lude; Wijmenga, Cisca; Barrett, Robert J.; Jonkers, Iris H.; Withoff, Sebo

doi:10.1016/j.celrep.2024.114247

Cited by 5 publications

(11 citation statements)

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“…TUBB2B, NCAM1 and RGMA) are enriched in Transwell systems [27][28][29] (Figures 5B-D). Accordingly, we observed more VIM-expressing epithelial cells in Transwell systems compared to organoids and intestine-on-chip systems, suggesting a potential epithelial-to-mesenchymal transition, as observed in a previous study 15 (Figure S1D). Genes specifically upregulated in intestine-on-chip systems (cluster 2) primarily included enterocyte-associated genes related to small intestinal functions such as nutrient metabolism (e.g.…”

Section: Enrichment Of Intestinal Functions and Enhanced Maturation O...supporting

confidence: 87%

“…Interestingly, in contrast to organoids, pathways and genes related to neurogenesis were upregulated (e.g. TUBB2B, NCAM1, CRABP2, ETV5, NRP1 and RGMA) in the EM condition in Transwell systems, which might correspond to previous observations of neuron development in a hiPSC-derived intestine-on-chip exposed to the same medium 15 (Figures 4B-C). Regardless of the limited number of EPCAM-negative cells, these mesenchymal and neural cell types might still be present at low levels and be specifically amplified in Transwell systems.…”

Section: Transcriptomic Analysis Confirms Enrichment Of Enterocyte-an...supporting

confidence: 86%

“…Overall, these principles can be applied to steer hiPSC-derived intestinal tissues toward a desired epithelial composition, regardless of the model system used. To balance epithelial proliferation and differentiation, and thus increase epithelial diversity and physiological relevance, basolateral exposure to the EM condition and apical exposure to a type of DM can be applied in both Transwell and intestine-on-chip systems 15 . The fact that this works in the static and dynamic environment of both systems demonstrates that continuous renewal of medium in a microfluidic system is not required.…”

Section: Discussionmentioning

confidence: 99%

“…All these epithelial subtypes showed similar trends in organoids and Transwell systems, except for LYZ-positive cells (Figures 1B-C). Based on the absence of defensin gene expression, these cells were assumed to resemble the Paneth-like cell population previously identified by our group in a hiPSC-intestine-on-chip 15 . While LYZpositive Paneth-like cells were present in all conditions except DM+D+P in Transwell systems, they were only detected in the EM condition in organoids, suggesting a differential sensitivity to the microenvironments of the organoids and Transwell systems (Figures 1B-C).…”

Section: Wnt Bmp Notch and Mapk Regulators Induce Specific Epithelial...mentioning

confidence: 99%

“…Lastly, we wanted to investigate the biological processes regulated by the culture environment of conventionally used intestinal model systems. We recently demonstrated that exposure to the EM-DM+D+P condition in a microfluidic hiPSC-derived intestine-on-chip system induces an epithelial composition that resembles the human small intestine 15 . Here, we compared the transcriptomic profiles of hiPSC-derived intestinal epithelial cells grown as organoids (exposed to DM+D+P), in Transwell systems and in a commercially available intestine-on-chip system (both exposed to EM-DM+D+P) (Figures 5A, S1C).…”

Section: Enrichment Of Intestinal Functions and Enhanced Maturation O...mentioning

confidence: 99%

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Intestine-on-chip enhances nutrient and drug metabolism and maturation of iPSC-derived intestinal epithelial cells relative to organoids and Transwells

Moerkens,

Mooiweer,

Smits

et al. 2024

Preprint

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The human intestinal epithelial barrier is shaped by various biological and biomechanical influences such as growth factor gradients and the flow of intestinal contents. Exposure to these cuesin vitroimpacts the cell type composition and function of adult stem cell (ASC)-derived intestinal epithelial cells, but their effect on human induced pluripotent stem cell (hiPSC)-derived cells is largely unexplored. Here, we characterize and compare the cellular composition and gene expression profiles of hiPSC-derived intestinal epithelial cells exposed to various medium compositions and cultured as organoids, in Transwell and in microfluidic intestine-on-chip systems. We demonstrate that inhibition and activation of the WNT, BMP, NOTCH and MAPK pathways regulates the presence of dividing, absorptive and secretory epithelial lineages within these systems, as has been described for ASC-based systems. Upon differentiation, intestinal epithelial organoids and monolayers in Transwell systems expressed genes involved in important intestinal functions, including digestive enzymes, nutrient transporters and members of the Cytochrome P450 family implicated in drug metabolism. However, the dynamic microenvironment of the intestine-on-chip system induced the strongest upregulation of these genes, with an expression profile that suggests a more mature developmental state. Overall, these results underscore the value of hiPSC-derived intestinal epithelial cells for modeling important functions of the human intestinal epithelial barrier and facilitates the selection of relevant culture conditions for specific applications.

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Section: Enrichment Of Intestinal Functions and Enhanced Maturation O...supporting

confidence: 87%

Section: Transcriptomic Analysis Confirms Enrichment Of Enterocyte-an...supporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Wnt Bmp Notch and Mapk Regulators Induce Specific Epithelial...mentioning

confidence: 99%

Section: Enrichment Of Intestinal Functions and Enhanced Maturation O...mentioning

confidence: 99%

See 3 more Smart Citations

Intestine-on-chip enhances nutrient and drug metabolism and maturation of iPSC-derived intestinal epithelial cells relative to organoids and Transwells

Moerkens,

Mooiweer,

Smits

et al. 2024

Preprint

Self Cite

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Leveraging Organ‐on‐Chip Models to Investigate Host–Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease

Kaden,

Alonso‐Román,

Stallhofer

et al. 2024

Adv Healthcare Materials

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Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host–microbiota interactions and stable long‐term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ‐on‐chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease‐driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host–microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota‐related therapies and personalized medicine for IBD treatment is discussed.

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Pluripotent stem cell‐derived organoids: A brief history of curiosity‐led discoveries

Lancaster

2024

BioEssays

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Organoids are quickly becoming an accepted model for understanding human biology and disease. Pluripotent stem cells (PSC) provide a starting point for many organs and enable modeling of the embryonic development and maturation of such organs. The foundation of PSC‐derived organoids can be found in elegant developmental studies demonstrating the remarkable ability of immature cells to undergo histogenesis even when taken out of the embryo context. PSC‐organoids are an evolution of earlier methods such as embryoid bodies, taken to a new level with finer control and in some cases going beyond tissue histogenesis to organ‐like morphogenesis. But many of the discoveries that led to organoids were not necessarily planned, but rather the result of inquisitive minds with freedom to explore. Protecting such curiosity‐led research through flexible funding will be important going forward if we are to see further ground‐breaking discoveries.

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An iPSC-derived small intestine-on-chip with self-organizing epithelial, mesenchymal, and neural cells

Cited by 5 publications

References 81 publications

Intestine-on-chip enhances nutrient and drug metabolism and maturation of iPSC-derived intestinal epithelial cells relative to organoids and Transwells

Intestine-on-chip enhances nutrient and drug metabolism and maturation of iPSC-derived intestinal epithelial cells relative to organoids and Transwells

Leveraging Organ‐on‐Chip Models to Investigate Host–Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease

Pluripotent stem cell‐derived organoids: A brief history of curiosity‐led discoveries

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