137 Conditional Deletion of Prep1 in the Intestinal Epithelium Alters Epithelial Homeostasis, Intestinal Development, and Controls Colitis Susceptibility

2014 ◽  
Vol 146 (5) ◽  
pp. S-38 ◽  
Author(s):  
Silvia D'Alessio ◽  
Carlotta Tacconi ◽  
Carmen Correale ◽  
Alessandro Gandelli ◽  
Marco Genua ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Intestinal Development ◽  
Epithelial Homeostasis ◽  
Conditional Deletion

scholarly journals LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

2020 ◽  
Vol 6 (37) ◽  
pp. eabc0367 ◽  
Author(s):  
Rosalie T. Zwiggelaar ◽  
Håvard T. Lindholm ◽  
Madeleine Fosslie ◽  
Marianne Terndrup Pedersen ◽  
Yuki Ohta ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Epithelial ◽  
Intestinal Development ◽  
Gene Profile ◽  
Epithelial Homeostasis ◽  
Lysine Specific Demethylase ◽  
Epithelial Development ◽  
Important Regulator

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

scholarly journals LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

2020 ◽  
Author(s):  
Rosalie T. Zwiggelaar ◽  
Håvard T. Lindholm ◽  
Madeleine Fosslie ◽  
Marianne T. Pedersen ◽  
Yuki Ohta ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Epithelial ◽  
Intestinal Development ◽  
Gene Profile ◽  
Epithelial Homeostasis ◽  
Lysine Specific Demethylase ◽  
Epithelial Development ◽  
Important Regulator

ABSTRACTIntestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that Lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 represses genes that are normally expressed in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and indeed, we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium towards a reparative state.

scholarly journals Cellular Composition and Differentiation Signaling in Chicken Small Intestinal Epithelium

Animals ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 870
Author(s):  
Haihan Zhang ◽  
Dongfeng Li ◽  
Lingbin Liu ◽  
Ling Xu ◽  
Mo Zhu ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Intestinal Development ◽  
Cell Culture Model ◽  
Proliferation Zone ◽  
Small Intestinal Epithelium ◽  
Culture Model ◽  
Different Types ◽  
Development And Differentiation ◽  
Small Intestinal

The small intestine plays an important role for animals to digest and absorb nutrients. The epithelial lining of the intestine develops from the embryonic endoderm of the embryo. The mature intestinal epithelium is composed of different types of functional epithelial cells that are derived from stem cells, which are located in the crypts. Chickens have been widely used as an animal model for researching vertebrate embryonic development. However, little is known about the molecular basis of development and differentiation within the chicken small intestinal epithelium. This review introduces processes of development and growth in the chicken gut, and compares the cellular characteristics and signaling pathways between chicken and mammals, including Notch and Wnt signaling that control the differentiation in the small intestinal epithelium. There is evidence that the chicken intestinal epithelium has a distinct cellular architecture and proliferation zone compared to mammals. The establishment of an in vitro cell culture model for chickens will provide a novel tool to explore molecular regulation of the chicken intestinal development and differentiation.

scholarly journals Long noncoding RNAs in intestinal epithelium homeostasis

2019 ◽  
Vol 317 (1) ◽  
pp. C93-C100 ◽  
Author(s):  
Lan Xiao ◽  
Myriam Gorospe ◽  
Jian-Ying Wang
Keyword(s):  
Intestinal Epithelium ◽  
Rna Binding ◽  
Noncoding Rnas ◽  
The Body ◽  
Long Noncoding Rnas ◽  
Biological Functions ◽  
Mucosal Regeneration ◽  
Epithelial Barrier Function ◽  
Epithelial Homeostasis ◽  
Stressful Environments

The epithelium of the mammalian intestinal mucosa is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through well-controlled mechanisms. Long noncoding RNAs (lncRNAs) regulate a variety of biological functions and are intimately involved in the pathogenesis of diverse human diseases. Here we highlight the roles of several lncRNAs expressed in the intestinal epithelium, including uc.173, SPRY4-IT1, H19, and Gata6, in maintaining the integrity of the intestinal epithelium, focusing on the emerging evidence of lncRNAs in the regulation of intestinal mucosal regeneration and epithelial barrier function. We also discuss recent results that the interactions between lncRNAs with microRNAs and the RNA-binding protein HuR influence epithelial homeostasis. With rapidly advancing knowledge of lncRNAs, there is also growing recognition that lncRNAs in the intestinal epithelium might be promising therapeutic targets in our efforts to protect the integrity of the intestinal epithelium in response to stressful environments.

scholarly journals Organoid-based modeling of intestinal development, regeneration, and repair

2020 ◽  
Vol 28 (1) ◽  
pp. 95-107
Author(s):  
Joep Sprangers ◽  
Irene C. Zaalberg ◽  
Madelon M. Maurice
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathways ◽  
Intestinal Epithelium ◽  
Tissue Remodeling ◽  
Intestinal Development ◽  
Regenerative Response ◽  
Key Players ◽  
Intestinal Repair ◽  
Homeostatic State

AbstractThe intestinal epithelium harbors a remarkable adaptability to undergo injury-induced repair. A key part of the regenerative response is the transient reprogramming of epithelial cells into a fetal-like state, which drives uniform proliferation, tissue remodeling, and subsequent restoration of the homeostatic state. In this review, we discuss how Wnt and YAP signaling pathways control the intestinal repair response and the transitioning of cell states, in comparison with the process of intestinal development. Furthermore, we highlight how organoid-based applications have contributed to the characterization of the mechanistic principles and key players that guide these developmental and regenerative events.

scholarly journals Chronic TNFα-driven injury delays cell migration to villi in the intestinal epithelium

2018 ◽  
Vol 15 (145) ◽  
pp. 20180037 ◽  
Author(s):  
Daniele Muraro ◽  
Aimee Parker ◽  
Laura Vaux ◽  
Sarah Filippi ◽  
Axel A. Almet ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Cell Tracking ◽  
Computational Models ◽  
Epithelial Stem Cells ◽  
Epithelial Homeostasis ◽  
The Impact ◽  
Epithelial Cell Death

The intestinal epithelium is a single layer of cells which provides the first line of defence of the intestinal mucosa to bacterial infection. Cohesion of this physical barrier is supported by renewal of epithelial stem cells, residing in invaginations called crypts, and by crypt cell migration onto protrusions called villi; dysregulation of such mechanisms may render the gut susceptible to chronic inflammation. The impact that excessive or misplaced epithelial cell death may have on villus cell migration is currently unknown. We integrated cell-tracking methods with computational models to determine how epithelial homeostasis is affected by acute and chronic TNFα-driven epithelial cell death. Parameter inference reveals that acute inflammatory cell death has a transient effect on epithelial cell dynamics, whereas cell death caused by chronic elevated TNFα causes a delay in the accumulation of labelled cells onto the villus compared to the control. Such a delay may be reproduced by using a cell-based model to simulate the dynamics of each cell in a crypt–villus geometry, showing that a prolonged increase in cell death slows the migration of cells from the crypt to the villus. This investigation highlights which injuries (acute or chronic) may be regenerated and which cause disruption of healthy epithelial homeostasis.

scholarly journals LRH-1 Mitigates Intestinal Inflammatory Disease by Maintaining Epithelial Homeostasis and Cell Survival

2018 ◽  
Author(s):  
James R. Bayrer ◽  
Hongtao Wang ◽  
Roy Nattiv ◽  
Miyuki Suzawa ◽  
Hazel S. Escusa ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Goblet Cells ◽  
Inflammatory Conditions ◽  
Epithelial Homeostasis ◽  
Inflammatory Damage ◽  
Intestinal Organoids ◽  
Current Therapies ◽  
Inflammatory Bowel ◽  
Intestinal Inflammatory Disease ◽  
Epithelial Dysfunction

Epithelial dysfunction and loss of intestinal crypts are defining features of inflammatory bowel disease (IBD). However, current therapies primarily target the immune system and not the epithelium. The nuclear receptor LRH-1 encoded by Nr5a2 is expressed in intestinal epithelium and is thought to contribute to epithelial renewal. Here we investigate how loss and gain of LRH-1 impacts the intestinal epithelium in healthy and inflammatory conditions. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death and weakens the epithelial barrier. Loss of LRH-1 also distorts the cellular composition of the epithelium, resulting in an expansion of Paneth and goblet cells, and a decrease in enteroendocrine cells. Human LRH-1 (hLRH-1) not only rescues epithelial integrity, but when overexpressed, mitigates inflammatory damage in mouse and human intestinal organoids, including those from IBD patients. Finally, hLRH-1 greatly reduces disease severity in a mouse model of T cell-mediated colitis. Together with the failure of a ligand-incompetent hLRH-1 mutant to protect against TNFα-damage, these findings provide compelling evidence that hLRH-1 mediates epithelial homeostasis and is an attractive target for intestinal disease.

scholarly journals The ‘de novo’ DNA methyltransferase Dnmt3b compensates the Dnmt1-deficient intestinal epithelium

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ellen N Elliott ◽  
Karyn L Sheaffer ◽  
Klaus H Kaestner
Keyword(s):  
Dna Methylation ◽  
Genomic Instability ◽  
Intestinal Epithelium ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Somatic Tissue ◽  
Intestinal Development ◽  
Genomic Integrity ◽  
Intestinal Health ◽  
Methylation State

Dnmt1 is critical for immediate postnatal intestinal development, but is not required for the survival of the adult intestinal epithelium, the only rapidly dividing somatic tissue for which this has been shown. Acute Dnmt1 deletion elicits dramatic hypomethylation and genomic instability. Recovery of DNA methylation state and intestinal health is dependent on the de novo methyltransferase Dnmt3b. Ablation of both Dnmt1 and Dnmt3b in the intestinal epithelium is lethal, while deletion of either Dnmt1 or Dnmt3b has no effect on survival. These results demonstrate that Dnmt1 and Dnmt3b cooperate to maintain DNA methylation and genomic integrity in the intestinal epithelium.

scholarly journals Protein arginine methyltransferase 1 regulates cell proliferation and differentiation in adult mouse adult intestine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lu Xue ◽  
Lingyu Bao ◽  
Julia Roediger ◽  
Yijun Su ◽  
Bingyin Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Intestinal Epithelium ◽  
Adult Stem Cells ◽  
Adult Mouse ◽  
Intestinal Development ◽  
Arginine Methyltransferase ◽  
Mouse Intestine ◽  
Protein Arginine Methyltransferase 1 ◽  
Crypt Base

Abstract Background Adult stem cells play an essential role in adult organ physiology and tissue repair and regeneration. While much has been learnt about the property and function of various adult stem cells, the mechanisms of their development remain poorly understood in mammals. Earlier studies suggest that the formation of adult mouse intestinal stem cells takes place during the first few weeks after birth, the postembryonic period when plasma thyroid hormone (T3) levels are high. Furthermore, deficiency in T3 signaling leads to defects in adult mouse intestine, including reduced cell proliferation in the intestinal crypts, where stem cells reside. Our earlier studies have shown that protein arginine methyltransferase 1 (PRMT1), a T3 receptor coactivator, is highly expressed during intestinal maturation in mouse. Methods We have analyzed the expression of PRMT1 by immunohistochemistry and studied the effect of tissue-specific knockout of PRMT1 in the intestinal epithelium. Results We show that PRMT1 is expressed highly in the proliferating transit amplifying cells and crypt base stem cells. By using a conditional knockout mouse line, we have demonstrated that the expression of PRMT1 in the intestinal epithelium is critical for the development of the adult mouse intestine. Specific removal of PRMT1 in the intestinal epithelium results in, surprisingly, more elongated adult intestinal crypts with increased cell proliferation. In addition, epithelial cell migration along the crypt-villus axis and cell death on the villus are also increased. Furthermore, there are increased Goblet cells and reduced Paneth cells in the crypt while the number of crypt base stem cells remains unchanged. Conclusions Our finding that PRMT1 knockout increases cell proliferation is surprising considering the role of PRMT1 in T3-signaling and the importance of T3 for intestinal development, and suggests that PRMT1 likely regulates pathways in addition to T3-signaling to affect intestinal development and/or homeostasis, thus affecting cell proliferating and epithelial turn over in the adult.

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