scholarly journals miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Algera Goga ◽  
Büsra Yagabasan ◽  
Karolin Herrmanns ◽  
Svenja Godbersen ◽  
Pamuditha N. Silva ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Cell Function ◽  
Paneth Cell ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Genetic Ablation ◽  
Epithelial Homeostasis ◽  
Enterocyte Differentiation

AbstractThe intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.

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 Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine

2006 ◽  
Vol 26 (13) ◽  
pp. 4949-4957 ◽  
Author(s):  
Andrea Haegebarth ◽  
Wenjun Bie ◽  
Ruyan Yang ◽  
Susan E. Crawford ◽  
Valeri Vasioukhin ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Fatty Acid Binding ◽  
Protein Tyrosine ◽  
Adult Mice ◽  
Enterocyte Differentiation

ABSTRACT Protein tyrosine kinase 6 (PTK6) (also called Brk or Sik) is an intracellular tyrosine kinase that is expressed in breast cancer and normal epithelial linings. In adult mice, PTK6 expression is high in villus epithelial cells of the small intestine. To explore functions of PTK6, we disrupted the mouse Ptk6 gene. We detected longer villi, an expanded zone of PCNA expression, and increased bromodeoxyuridine incorporation in the PTK6-deficient small intestine. Although differentiation of major epithelial cell types occurred, there was a marked delay in expression of intestinal fatty acid binding protein, suggesting a role for PTK6 in enterocyte differentiation. However, fat absorption was comparable in wild-type and Ptk6 −/− mice. It was previously shown that the serine threonine kinase Akt is a substrate of PTK6 and that PTK6-mediated phosphorylation of Akt on tyrosine resulted in inhibition of Akt activity. Consistent with these findings, we detected increased Akt activity and nuclear β-catenin in intestines of PTK6-deficient mice and decreased nuclear localization of the Akt substrate FoxO1 in villus epithelial cells. PTK6 contributes to maintenance of tissue homeostasis through negative regulation of Akt in the small intestine and is associated with cell cycle exit and differentiation in normal intestinal epithelial cells.

scholarly journals Functional transcriptomics in diverse intestinal epithelial cell types reveals robust gut microbial sensitivity of microRNAs in intestinal stem cells

2016 ◽  
Author(s):  
Bailey C. E. Peck ◽  
Amanda T. Mah ◽  
Wendy A. Pitman ◽  
Shengli Ding ◽  
P. Kay Lund ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Mirna Expression ◽  
Intestinal Epithelial Cell ◽  
Ex Vivo ◽  
Cell Types ◽  
Gastrointestinal Diseases ◽  
Host Immune System ◽  
Intestinal Epithelial ◽  
Novel Therapeutic Strategies

ABSTRACTGut microbiota play an important role in regulating the development of the host immune system, metabolic rate, and at times, disease pathogenesis. The factors and mechanisms that mediate communication between microbiota and the intestinal epithelium are poorly understood. We provide novel evidence that microbiota may control intestinal epithelial stem cell (IESC) proliferation in part through microRNAs (miRNAs). We demonstrate that miRNA profiles differ dramatically across functionally distinct cell types of the mouse jejunal intestinal epithelium and that miRNAs respond to microbiota in a highly cell-type specific manner. Importantly, we also show that miRNAs in IESCs are more prominently regulated by microbiota compared to miRNAs in any other intestinal epithelial cell (IEC) subtype. We identify miR-375 as one miRNA that is significantly suppressed by the presence of microbiota in IESCs. Using a novel method to knockdown gene and miRNA expression ex vivo enteroids, we demonstrate that we can knockdown gene expression in Lgr5+ IESCs. Furthermore, when we knockdown miR-375 in IESCs, we observe significantly increased proliferative capacity. Understanding the mechanisms by which microbiota regulate miRNA expression in IESCs and other IEC subtypes will elucidate a critical molecular network that controls intestinal homeostasis and, given the heightened interest in miRNA-based therapies, may offer novel therapeutic strategies in the treatment of gastrointestinal diseases associated with altered IESC function.

scholarly journals Modeling Intestinal Stem Cell Function with Organoids

2021 ◽  
Vol 22 (20) ◽  
pp. 10912
Author(s):  
Toshio Takahashi ◽  
Kazuto Fujishima ◽  
Mineko Kengaku
Keyword(s):  
Small Intestine ◽  
Cell Function ◽  
Cell Types ◽  
Great Promise ◽  
Epithelial Tissue ◽  
Intestinal Epithelial ◽  
Cholinergic Signaling ◽  
New Treatments ◽  
Efficient Expansion

Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized by the presence of crypt-villus units that are in a state of homeostatic cell turnover. Organoid technology enables an efficient expansion of intestinal epithelial tissue in vitro. Thus, organoids hold great promise for use in medical research and in the development of new treatments. At present, the cholinergic system involved in IECs and intestinal stem cells (ISCs) are attracting a great deal of attention. Thus, understanding the biological processes triggered by epithelial cholinergic activation by acetylcholine (ACh), which is produced and released from neuronal and/or non-neuronal tissue, is of key importance. Cholinergic signaling via ACh receptors plays a pivotal role in IEC growth and differentiation. Here, we discuss current views on neuronal innervation and non-neuronal control of the small intestinal crypts and their impact on ISC proliferation, differentiation, and maintenance. Since technology using intestinal organoid culture systems is advancing, we also outline an organoid-based organ replacement approach for intestinal diseases.

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 An INF-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Iris Stolzer ◽  
Anja Dressel ◽  
Mircea T. Chiriac ◽  
Markus F. Neurath ◽  
Claudia Günther
Keyword(s):  
Cell Death ◽  
Small Intestine ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Cell Function ◽  
Paneth Cell ◽  
Intestinal Epithelial ◽  
Jak Inhibitors ◽  
Inflammatory Bowel ◽  
Epithelial Cell Death

Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8ΔIEC mice). Deletion of STAT1 in Casp8ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.

scholarly journals Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Jonathan H. M. van der Meer ◽  
Ruben J. de Boer ◽  
Bartolomeus J. Meijer ◽  
Wouter L. Smit ◽  
Jacqueline L. M. Vermeulen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Intestinal Epithelium ◽  
De Novo ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Argininosuccinate Synthetase ◽  
Important Amino Acid ◽  
Tissue Specimens ◽  
Colorectal Cancer Patients

AbstractThe epithelial signaling pathways involved in damage and regeneration, and neoplastic transformation are known to be similar. We noted upregulation of argininosuccinate synthetase (ASS1) in hyperproliferative intestinal epithelium. Since ASS1 leads to de novo synthesis of arginine, an important amino acid for the growth of intestinal epithelial cells, its upregulation can contribute to epithelial proliferation necessary to be sustained during oncogenic transformation and regeneration. Here we investigated the function of ASS1 in the gut epithelium during tissue regeneration and tumorigenesis, using intestinal epithelial conditional Ass1 knockout mice and organoids, and tissue specimens from colorectal cancer patients. We demonstrate that ASS1 is strongly expressed in the regenerating and Apc-mutated intestinal epithelium. Furthermore, we observe an arrest in amino acid flux of the urea cycle, which leads to an accumulation of intracellular arginine. However, loss of epithelial Ass1 does not lead to a reduction in proliferation or increase in apoptosis in vivo, also in mice fed an arginine-free diet. Epithelial loss of Ass1 seems to be compensated by altered arginine metabolism in other cell types and the liver.

scholarly journals Expression of MUC2 and MUC3 mRNA in human normal, malignant, and inflammatory intestinal tissues.

1996 ◽  
Vol 44 (10) ◽  
pp. 1161-1166 ◽  
Author(s):  
A A Weiss ◽  
M W Babyatsky ◽  
S Ogata ◽  
A Chen ◽  
S H Itzkowitz
Keyword(s):  
Small Intestine ◽  
Cell Function ◽  
Genetic Regulation ◽  
Constitutive Expression ◽  
Surface Epithelium ◽  
Intestinal Epithelial ◽  
Colon Cancers ◽  
Entire Height ◽  
Bowel Diseases ◽  
Well Differentiated

MUC2 and MUC3 are prominent mucin genes expressed in the human intestine. Using in situ hybridization with RNA probes, we examined the cellular distribution of MUC2 and MUC3 mRNA in normal, malignant, and inflammatory human intestinal tissues. In normal small intestine and colon, MUC2 mRNA was expressed exclusively in goblet cells and occurred throughout the entire height of the mucosa. MUC3 mRNA was expressed by goblet and columnar cells but was restricted to the villous compartment of the small intestine and the surface epithelium of the colon. Expression of MUC2 and MUC3 mRNA were both markedly decreased in poorly, moderately, and well-differentiated colon cancers but were preserved in mucinous colon cancers. In ulcerative colitis and Crohn's colitis tissues, MUC2 and MUC3 mRNA expression displayed a normal pattern regardless of whether the mucosa manifested active or quiescent inflammation. These findings indicate that MUC2 is goblet cell-specific, whereas MUC3 is related to maturation of intestinal epithelial cells. In colon cancers, the genetic regulation of MUC2 and MUC3 is different depending on the histological type of tumor. The constitutive expression of MUC2 and MUC3 mRNA in inflammatory bowel diseases suggests that these genes may be necessary for maintenance of normal epithelial cell function during inflammation.

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