<i>In Vitro</i> Generation of Mouse Colon Crypts

Wang, Yuli; Gunasekara, Dulan B.; Attayek, Peter J.; Reed, Mark I.; DiSalvo, Matthew; Nguyen, Daniel L.; Dutton, Johanna; Lebhar, Michael; Bultman, Scott J.; Sims, Christopher E.; Magness, Scott T.; Allbritton, Nancy L.

doi:10.1021/acsbiomaterials.7b00368

Cited by 23 publications

(29 citation statements)

References 41 publications

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“…Although monolayers were used for this initial demonstration, the device can also accommodate 3D cryptcontaining tissue-engineered mucosal barrier structures such as those previously described. 128 Overall, this platform faithfully recapitulates several important features of the physiological microenvironment in the colon in vivo and has the potential to enable a better understanding of human colon mucosal barrier-bacteria interactions. Given the reported difficulties on translating microbiome/bacteria-based therapy from animal models to human recently, 129,130 GuMI could help better understanding the inconsistency on the translation.…”

Section: Discussionmentioning

confidence: 94%

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Zhang

Huang

Yoon

et al. 2020

Preprint

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AbstractThe gut microbiome plays an important role in human health and disease. Gnotobiotic animal and in vitro cell-based models provide some informative insights into mechanistic crosstalk. However, there is no existing system for a chronic co-culture of a human colonic mucosal barrier with super oxygen-sensitive commensal microbes, hindering the study of human-microbe interactions in a controlled manner. Here, we investigated the effects of an abundant super oxygen-sensitive commensal anaerobe, Faecalibacterium prausnitzii, on a primary human mucosal barrier using a Gut-MIcrobiome (GuMI) physiome platform that we designed and fabricated. Chronic continuous co-culture of F. prausnitzii for two days with colon epithelia, enabled by continuous flow of completely anoxic apical media and aerobic basal media, resulted in a strictly anaerobic apical environment fostering growth of and butyrate production by F. prausnitzii, while maintaining a stable colon epithelial barrier. We identified elevated differentiation and hypoxia-responsive genes and pathways in the platform compared with conventional aerobic static culture of the colon epithelia, attributable to a combination of anaerobic environment and continuous medium replenishment. Furthermore, we demonstrated anti-inflammatory effects of F. prausnitzii through HDAC and the TLR-NFKB axis. Finally, we identified that butyrate largely contributes to the anti-inflammatory effects by downregulating TLR3 and TLR4. Our results are consistent with some clinical observations regarding F. prausnitzii, thus motivating further studies employing this platform with more complex engineered colon tissues for understanding the interaction between the human colonic mucosal barrier and microbiota, pathogens, or engineered bacteria.

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Section: Discussionmentioning

confidence: 94%

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Zhang

Huang

Yoon

et al. 2020

Preprint

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“…Despite the plethora of gradient-making technologies, only a limited number of these technologies and platforms have been applied successfully to primary intestinal epithelial models. 101 , 102 , 103 Most intestine- (or gut)-on-a-chip models use tumor cell lines, which are unlikely to respond in a physiologically relevant way to in vitro gradients or to form a physiologically normal niche. Given the richness and diversity of gradients formed across the intestinal epithelium, tremendous opportunities exist in the pairing of primary intestinal culture systems with chemical and matrix gradients.…”

Section: Discussionmentioning

confidence: 99%

“…A modified version has been paired with a shaped collagen scaffold to re-create arrays of polarized in vitro crypts and villi ( Figure 2 A and B ). 23 , 101 , 102 , 103 Microwells (crypts) and posts (villi) were fabricated into a collagen scaffold to mimic the shape, size, and density of crypts in vivo. Primary human and murine epithelial cells were expanded as monolayers and then placed under a gradient of growth factors including Wnt, R-spondin, and Noggin, resulting in a polarized epithelium with stem/proliferative cells isolated to the base of the microwells and differentiated cells localized to the luminal surface or villi of the scaffolding.…”

Section: Engineered In Vitro Gradientsmentioning

confidence: 99%

Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche

Wang

Kim

Hinman

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

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The relationship between intestinal stem cells (ISCs) and the surrounding niche environment is complex and dynamic. Key factors localized at the base of the crypt are necessary to promote ISC self-renewal and proliferation, to ultimately provide a constant stream of differentiated cells to maintain the epithelial barrier. These factors diminish as epithelial cells divide, migrate away from the crypt base, differentiate into the postmitotic lineages, and end their life span in approximately 7 days when they are sloughed into the intestinal lumen. To facilitate the rapid and complex physiology of ISC-driven epithelial renewal, in vivo gradients of growth factors, extracellular matrix, bacterial products, gases, and stiffness are formed along the crypt-villus axis. New bioengineered tools and platforms are available to recapitulate various gradients and support the stereotypical cellular responses associated with these gradients. Many of these technologies have been paired with primary small intestinal and colonic epithelial cells to re-create select aspects of normal physiology or disease states. These biomimetic platforms are becoming increasingly sophisticated with the rapid discovery of new niche factors and gradients. These advancements are contributing to the development of high-fidelity tissue constructs for basic science applications, drug screening, and personalized medicine applications. Here, we discuss the direct and indirect evidence for many of the important gradients found in vivo and their successful application to date in bioengineered in vitro models, including organ-on-chip and microfluidic culture devices.

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“…Specifically, these research articles were related to the topics, including drug toxicology, 14 biomaterials, 15 organogenesis, 16 and 3D printing. 17,18 Besides, Lab on a Chip (n = 4) was ranked first in the source journals of these 50 documents.…”

Section: Clear Imbalance In the Distribution Of Contributing Partiesmentioning

confidence: 99%

Global Trends of Organoid and Organ-On-a-Chip in the Past Decade: A Bibliometric and Comparative Study

Wang

Qiao

et al. 2020

Tissue Engineering Part A

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Organoid and organ-on-a-chip have evolved as two critical but distinct approaches to develop human physiologically and pathologically relevant in vitro models. Although rapid progress has been witnessed in the past decade, there is no systematic comparison of their status and trends based on the scientometric analysis. In this study, we performed a comparative study of organoid and organ-on-a-chip using bibliometric methods. A total of 2790 documents published between 2009 and 2018 were retrieved and analyzed. Our results showed that both organoid and organ-on-a-chip had experienced rapid growth in their academic and social impacts and influenced a wide spectrum of disciplines, but with a major distinct focus on Cell Biology and Nanoscience Nanotechnology, respectively. The hotspots of organoid research were expanding from in vitro differentiation of Lgr5 stem cells to mechanistic studies of diseases, while the hotspots of the organ-on-a-chip research were transiting from the establishment of microfluidic devices for in vitro cell culture to stem cell differentiation and tissue engineering. Interestingly, there was a growing trend of combining organoid with organ-on-a-chip in the last few years. This comparative study presented a unique perspective to understand the evolutive history and future trends of organoid and organ-on-a-chip for emerging human relevant in vitro organotypic models.

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In Vitro Generation of Mouse Colon Crypts

Cited by 23 publications

References 41 publications

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture

Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche

Global Trends of Organoid and Organ-On-a-Chip in the Past Decade: A Bibliometric and Comparative Study

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