Cell differentiation is disrupted by MYO5B loss through Wnt/Notch imbalance

Kaji, Izumi; Roland, Joseph T.; Kumar, Sudiksha Rathan; Engevik, Amy C.; Burman, Andreanna; Goldstein, Anna E.; Watanabe, Masahiko; Goldenring, James R.

doi:10.1172/jci.insight.150416

Cited by 19 publications

(21 citation statements)

References 38 publications

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“…Fig. S6A), we can roughly model these as circles with a radius of 8.4µm, yielding an area of ∼55.4µm Target cell frequency in the model was estimated based on our own observations and the published work of others 53,54 that showed goblet cells represent between 4-12% of epithelial cells in the mouse small intestine.…”

Section: Supplemental Materials Supplemental Methodsmentioning

confidence: 99%

“…Target cell frequency in the model was estimated based on our own observations and the published work of others 53,54 that showed goblet cells represent between 4-12% of epithelial cells in the mouse small intestine. Varying target cell percentage within this range has only modest effects on model outcomes as the epithelium is relatively static compared to the phagocytes/bacteria.…”

Section: Supplemental Materialsmentioning

confidence: 99%

“…Cells were initialized as circles with a 6-pixel radius and, before the start of the simulation, allowed to equilibrate for 20 MCS to expand and cover the entire grid. N goblet cells were then randomly appointed target cells representing “goblet cells” that can potentially be invaded by bacteria unless otherwise mentioned, we used N goblet = 20 so that 7% of the epithelial surface is occupied by goblet cells, which is within range of experimental values 53 .…”

Section: Supplemental Materialsmentioning

confidence: 99%

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Listeria motility increases the efficiency of goblet cell invasion during intestinal infection

Wortel

Kim

Liu

et al. 2022

Preprint

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Listeria monocytogenes (Lm) is a food-borne pathogen that causes severe bacterial gastroenteritis, with high rates of hospitalization and mortality. Lm is ubiquitous in soil, water and livestock, and can survive and proliferate at low temperatures. Following oral ingestion of contaminated food, Lm crosses the epithelial through intestinal goblet cells in a mechanism depending on Lm InlA and host E-cadherin. Importantly, human infections typically occur with Lm growing at or below room temperature, which are flagellated and motile. Even though many important human bacterial pathogens are flagellated, little is known regarding the effect of bacterial motility on invasion and immune evasion. Here, we used complementary imaging and computer modeling approaches to test the hypothesis that bacterial motility helps Lm locate and engage target cells permissive for invasion. Imaging explanted mouse and human intestine, we confirmed that Lm grown at room temperature uses motility to scan the epithelial surface and preferentially attach to target cells. Furthermore, we integrated quantitative parameters from our imaging experiments to construct a versatile "layered" cellular Potts model (L-CPM) that simulates host-pathogen dynamics. Simulated data are consistent with the hypothesis that bacterial motility enhances invasion by allowing bacteria to search the epithelial surface for their preferred invasion targets. Indeed, our model consistently predicts that motile bacteria have invaded ~2-fold more at the 1-hour mark. This invasion advantage persists even in the presence of host phagocytes, with the balance between invasion and phagocytosis governed almost entirely by bacterial motility. In conclusion, our simulations provide insight into host pathogen interactions and challenge fundamental assumptions regarding how phagocytes might limit bacterial invasion early during infection.

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Section: Supplemental Materials Supplemental Methodsmentioning

confidence: 99%

Section: Supplemental Materialsmentioning

confidence: 99%

Section: Supplemental Materialsmentioning

confidence: 99%

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Listeria motility increases the efficiency of goblet cell invasion during intestinal infection

Wortel

Kim

Liu

et al. 2022

Preprint

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“…Fluid, electrolyte and acid/base management in MYO5B deficiency remains extremely challenging to manage and symptomatic therapies such as chloride channel blocking anti-diarrheal drugs may prove useful. Several promising leads have recently emerged from mouse models of MVID including lysophosphatidic acid and the Wnt/Notch pathway (Kaji et al 2020(Kaji et al , 2021. The next stage for this very severe and life-limiting disease is to advance and discover disease-modifying therapies that can restore even some amount of intestinal absorptive function.…”

Section: Microvillus Inclusion Disease and Myo5bmentioning

confidence: 99%

The genetics of monogenic intestinal epithelial disorders

2022

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Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.

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“… 104 , 105 Deletion of MYO5B impairs precursor differentiation into organoids and partially mediates Wnt/Notch imbalance, and Notch inhibition and/or LPA treatment could be an effective treatment for MVID. 106 Diacylglycerol-acyltransferase 1 (DGAT1) dysfunction often leads to another rare, intractable form of malabsorption and diarrheal disease that appears early in life. 107 The main role of DGAT1 is to catalyze the conversion of diglycerides and fatty acyl-CoA to triglycerides, and DGAT1 deficiency can lead to fat intolerance and protein-losing enteropathy.…”

Section: The Application Of Organoidsmentioning

confidence: 99%

Applications of human organoids in the personalized treatment for digestive diseases

Wang

Guo

Jin

et al. 2022

Sig Transduct Target Ther

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Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.

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Cell differentiation is disrupted by MYO5B loss through Wnt/Notch imbalance

Cited by 19 publications

References 38 publications

Listeria motility increases the efficiency of goblet cell invasion during intestinal infection

Listeria motility increases the efficiency of goblet cell invasion during intestinal infection

The genetics of monogenic intestinal epithelial disorders

Applications of human organoids in the personalized treatment for digestive diseases

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