scholarly journals T helper cells modulate intestinal stem cell renewal and differentiation

2017 ◽  
Author(s):  
Moshe Biton ◽  
Adam L. Haber ◽  
Semir Beyaz ◽  
Noga Rogel ◽  
Christopher Smillie ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Epithelial Cells ◽  
Immune Cell ◽  
Intestinal Epithelial Cells ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
T Helper ◽  
Self Renewal

AbstractIn the small intestine, a cellular niche of diverse accessory cell types supports the rapid generation of mature epithelial cell types through self-renewal, proliferation, and differentiation of intestinal stem cells (ISCs). However, not much is known about interactions between immune cells and ISCs, and it is unclear if and how immune cell dynamics affect eventual ISC fate or the balance between self-renewal and differentiation. Here, we used single-cell RNA-seq (scRNA-Seq) of intestinal epithelial cells (IECs) to identify new mechanisms for ISC–immune cell interactions. Surprisingly, MHC class II (MHCII) is enriched in two distinct subsets of Lgr5+ crypt base columnar ISCs, which are also distinguished by higher proliferation rates. Using co-culture of T cells with intestinal organoids, cytokine stimulations, and in vivo mouse models, we confirm that CD4+ T helper (Th) cells communicate with ISCs and affect their differentiation, in a manner specific to the Th subtypes and their signature cytokines and dependent on MHCII expression by ISCs. Specific inducible knockout of MHCII in intestinal epithelial cells in mice in vivo results in expansion of the ISC pool. Mice lacking T cells have expanded ISC pools, whereas specific depletion of Treg cells in vivo results in substantial reduction of ISC numbers. Our findings show that interactions between Th cells and ISCs mediated via MHCII expressed in intestinal epithelial stem cells help orchestrate tissue-wide responses to external signals.

scholarly journals Intestinal epithelial CD98 synthesis specifically modulates expression of colonic microRNAs during colitis

2012 ◽  
Vol 302 (11) ◽  
pp. G1282-G1291 ◽  
Author(s):  
Moiz A. Charania ◽  
Saravanan Ayyadurai ◽  
Sarah A. Ingersoll ◽  
Bo Xiao ◽  
Emilie Viennois ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mirna Expression ◽  
Target Genes ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Small Noncoding Rnas

The transmembrane glycoprotein CD98 is known to be involved in intestinal inflammation. In the present study, we found that CD98 overexpression in intestinal epithelial cells does not normally affect the expression of colonic (epithelial and immune cell) microRNAs (miRNAs), small noncoding RNAs that posttranscriptionally regulate a wide variety of biological processes. However, upon dextran sulfate sodium (DSS) treatment, the expression of several colonic miRNAs, but not miRNAs from other tissues such as liver and spleen, were differentially regulated in mice overexpressing CD98 in epithelial cells compared with wild-type (WT) animals. For example, the level of colonic miRNA 132 was not affected by DSS treatment in WT animals but was upregulated in mice overexpressing CD98 in intestinal epithelial cells. Other colonic miRNAs, including colonic miRNA 23a and 23b, were downregulated in WT animals after DSS treatment but not in colonic epithelial cell CD98-overexpressing mice. Interestingly, the expression of potential miRNA target genes affected intestinal epithelial cells that overexpress CD98 and cell types that did not overexpress CD98 but were in close proximity to CD98-overexpressing intestinal epithelial cells. Taken together, these observations show that the combination of an inflammatory context and intestinal epithelial cell expression of CD98 affects the regulation of miRNA expression in colonic epithelial and immune cells. This is new evidence that protein expression modulates miRNA expression and suggests the existence of regulatory crosstalk between proteins and miRNAs in diseases such as colitis.

scholarly journals Doxorubicin Induces Senescence in Intestinal Epithelial Cells

2021 ◽  
Author(s):  
Mandy Biraud ◽  
Jocsa Cortes ◽  
Paul Cray ◽  
Guy Kunzmann ◽  
Javid Mohammed ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Homogeneous Population ◽  
Doxorubicin Treatment ◽  
Induced Apoptosis

AbstractDoxorubicin treatment induces DNA damage and apoptosis in rapidly dividing cell types like intestinal epithelial cells. This has been demonstrated both in vivo and in vitro. In certain cell types some cells do not undergo DNA damage-induced apoptosis in response to doxorubicin but instead become senescent. Induction of senescence in these cells can lead to dysfunction and chronic inflammation, which can lead to more damage. We questioned whether a single dose of doxorubicin would be able to induce apoptosis and senescence in intestinal epithelial cells in vitro. For these studies, we exposed IEC-6 small intestinal epithelial cells to doxorubicin to evaluate whether senescence is induced in a relatively homogeneous population of intestinal epithelial cells. Although some cells underwent apoptosis, those that did not showed traits of senescence. Our studies showed that doxorubicin treatment increased cell size and increased expression of senescence-associated β-galactosidase. Concomitantly, we observed increased mRNA expression of several genes associated with a senescence-associated secretory phenotype including IL-6, Ptges, Faim2, and Cdkn1a and decreased expression of Sirt1. We also observed release of HMGB1, a cellular alarmin, from treated cells. Together, these data suggest that doxorubicin induces senescence in intestinal epithelial cells. Furthermore, our data indicate that cellular responses to a DNA damaging agent, such as doxorubicin, can differ within a population of cells suggesting differing levels of sensitivity within a relatively homogenous cell population. Further studies are needed to delineate the mechanisms that determine whether a cell moves down an apoptotic or senescent pathway following DNA damage.

scholarly journals Arid1a is essential for intestinal stem cells through Sox9 regulation

2019 ◽  
Vol 116 (5) ◽  
pp. 1704-1713 ◽  
Author(s):  
Yukiko Hiramatsu ◽  
Akihisa Fukuda ◽  
Satoshi Ogawa ◽  
Norihiro Goto ◽  
Kozo Ikuta ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Functional Role ◽  
Molecular Mechanisms ◽  
Intestinal Epithelial Cells ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Intestinal Homeostasis ◽  
Self Renewal

Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a. Lineage-tracing experiments revealed that Arid1a deletion in Lgr5+ ISCs leads to impaired self-renewal of Lgr5+ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5+ ISCs restores self-renewal in Arid1a-deleted Lgr5+ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.

Production of MDC/CCL22 by human intestinal epithelial cells

2001 ◽  
Vol 280 (6) ◽  
pp. G1217-G1226 ◽  
Author(s):  
M. Cecilia Berin ◽  
Michael B. Dwinell ◽  
Lars Eckmann ◽  
Martin F. Kagnoff
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Human Colon ◽  
Th2 Cytokines ◽  
Intestinal Epithelial ◽  
Apical Side ◽  
Constitutive Production ◽  
Factor Α

The intestinal mucosa contains a subset of lymphocytes that produce Th2 cytokines, yet the signals responsible for the recruitment of these cells are poorly understood. Macrophage-derived chemokine (MDC/CCL22) is a recently described CC chemokine known to chemoattract the Th2 cytokine producing cells that express the receptor CCR4. The studies herein demonstrate the constitutive production of MDC/CCL22 in vivo by human colon epithelium and by epithelium of human intestinal xenografts. MDC/CCL22 mRNA expression and protein secretion was upregulated in colon epithelial cell lines in response to proinflammatory cytokines or infection with enteroinvasive bacteria. Inhibition of nuclear factor (NF)-κB activation abolished MDC/CCL22 expression in response to proinflammatory stimuli, demonstrating that MDC/CCL22 is a NF-κB target gene. In addition, tumor necrosis factor-α-induced MDC/CCL22 secretion was differentially modulated by Th1 and Th2 cytokines. Supernatants from the basal, but not apical, side of polarized epithelial cells induced a MDC/CCL22-dependent chemotaxis of CCR4-positive T cells. These studies demonstrate the constitutive and regulated production by intestinal epithelial cells of a chemokine known to function in the trafficking of T cells that produce anti-inflammatory cytokines.

scholarly journals Dkk-1 Inhibits Intestinal Epithelial Cell Migration by Attenuating Directional Polarization of Leading Edge Cells

2009 ◽  
Vol 20 (22) ◽  
pp. 4816-4825 ◽  
Author(s):  
Stefan Koch ◽  
Christopher T. Capaldo ◽  
Stanislav Samarin ◽  
Porfirio Nava ◽  
Irmgard Neumaier ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Leading Edge ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Microtubule Organizing Center ◽  
Organizing Center ◽  
Interfering Rna

Wnt signaling pathways regulate proliferation, motility, and survival in a variety of human cell types. Dickkopf-1 (Dkk-1) is a secreted Wnt antagonist that has been proposed to regulate tissue homeostasis in the intestine. In this report, we show that Dkk-1 is secreted by intestinal epithelial cells after wounding and that it inhibits cell migration by attenuating the directional orientation of migrating epithelial cells. Dkk-1 exposure induced mislocalized activation of Cdc42 in migrating cells, which coincided with a displacement of the polarity protein Par6 from the leading edge. Consequently, the relocation of the microtubule organizing center and the Golgi apparatus in the direction of migration was significantly and persistently inhibited in the presence of Dkk-1. Small interfering RNA-induced down-regulation of Dkk-1 confirmed that extracellular exposure to Dkk-1 was required for this effect. Together, these data demonstrate a novel role of Dkk-1 in the regulation of directional polarization of migrating intestinal epithelial cells, which contributes to the effect of Dkk-1 on wound closure in vivo.

Luminal antigens access late endosomes of intestinal epithelial cells enriched in MHC I and MHC II molecules: in vivo study in Crohn's ileitis

2007 ◽  
Vol 293 (4) ◽  
pp. G798-G808 ◽  
Author(s):  
Gheorghe Hundorfean ◽  
Klaus-Peter Zimmer ◽  
Stephan Strobel ◽  
Andreas Gebert ◽  
Diether Ludwig ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Antigen Processing ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Mhc I ◽  
Mhc Ii ◽  
Late Endosomes ◽  
Early Endosomes

In contrast to healthy conditions, intestinal epithelial cells (IECs) stimulate proinflammatory CD4+and CD8+T cells during Crohn's disease (CD). The underlying regulatory mechanisms remain unknown. Here we investigated the epithelial expression of major histocompatibility complex (MHC) I and MHC II and its interference with endocytic pathways, in vivo. During ileoscopy, ovalbumin (OVA) was sprayed onto ileal mucosa of CD patients (ileitis and remission) and controls. The epithelial traffic of OVA and MHC I/II pathways were studied in biopsies using fluorescence and electron microscopy. We found MHC I and MHC II to accumulate within multivesicular late endosomes (MVLE) of IECs. Faint labeling for these molecules was seen in early endosomes and lysosomes. MVLE were entered by OVA 10 min after exposure. Exosomes carrying MHC I, MHC II, and OVA were detected in intercellular spaces of the epithelium. OVA trafficking and labeling patterns for MHC I and MHC II in IECs showed no differences between CD patients and controls. Independent of inflammatory stimuli, MHC I and MHC II pathways intersect MVLE in IECs, which were efficiently targeted by luminal antigens. Similar to MHC II-enriched compartments in professional antigen presenting cells, these MVLE might be critically involved in MHC I- and MHC II-related antigen processing in IECs and the source of epithelial-released exosomes. The access of luminal antigens to MHC I in MVLE might indicate that the presentation of exogenous antigens by IECs must not be restricted to MHC II but might also occur as “cross-presentation” via MHC I to CD8+T cells.

scholarly journals Immunoregulatory Effects of Porcine Plasma Protein Concentrates on Rat Intestinal Epithelial Cells and Splenocytes

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 807
Author(s):  
Cristina Hernández-Chirlaque ◽  
Carlos J. Aranda ◽  
Borja Ocón ◽  
Javier Polo ◽  
Olga Martínez-Augustin ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Plasma Protein ◽  
Intestinal Epithelial Cells ◽  
Primary Cultures ◽  
Cell Types ◽  
Epithelial Cell Line ◽  
Intestinal Epithelial ◽  
Protein Concentrates ◽  
Specific Effects

Serum protein concentrates have been shown to exert in vivo anti-inflammatory effects. Specific effects on different cell types and their mechanism of action remain unraveled. We aimed to characterize the immunomodulatory effect of two porcine plasma protein concentrates, spray dried serum (SDS) and an immunoglobulin concentrate (IC), currently used as animal nutritional supplements with established in vivo immunomodulatory properties. Cytokine production by the intestinal epithelial cell line IEC18 and by primary cultures of rat splenocytes was studied. The molecular pathways involved were explored with specific inhibitors and gene knockdown. Our results indicate that both products induced GROα and MCP-1 production in IEC18 cells by a MyD88/NF-κB-dependent mechanism. Inhibition of TNF production was observed in rat primary splenocyte cultures. The immunoglobulin concentrate induced IL-10 expression in primary splenocytes and lymphocytes. The effect on TNF was independent of IL-10 production or the stimulation of NF-kB, MAPKs, AKT, or RAGE. In conclusion, SDS and IC directly regulate intestinal and systemic immune response in murine intestinal epithelial cells and in T lymphocytes and monocytes.

scholarly journals Expression of lysophosphatidic acid receptor 5 is necessary for the regulation of intestinal Na+/H+ exchanger 3 by lysophosphatidic acid in vivo

2018 ◽  
Vol 315 (4) ◽  
pp. G433-G442 ◽  
Author(s):  
Kayte A. Jenkin ◽  
Peijian He ◽  
C. Chris Yun
Keyword(s):  
Epithelial Cells ◽  
Lysophosphatidic Acid ◽  
Direct Evidence ◽  
Intestinal Epithelial Cells ◽  
Regulatory Role ◽  
Intestinal Epithelial ◽  
Fluid Absorption ◽  
Wild Type

Lysophosphatidic acid (LPA) is a bioactive lipid molecule, which regulates a broad range of pathophysiological processes. Recent studies have demonstrated that LPA modulates electrolyte flux in the intestine, and its potential as an antidiarrheal agent has been suggested. Of six LPA receptors, LPA5 is highly expressed in the intestine. Recent studies by our group have demonstrated activation of Na+/H+ exchanger 3 (NHE3) by LPA5. However, much of what has been elucidated was achieved using colonic cell lines that were transfected to express LPA5. In the current study, we engineered a mouse that lacks LPA5 in intestinal epithelial cells, Lpar5ΔIEC, and investigated the role of LPA5 in NHE3 regulation and fluid absorption in vivo. The intestine of Lpar5ΔIEC mice appeared morphologically normal, and the stool frequency and fecal water content were unchanged compared with wild-type mice. Basal rates of NHE3 activity and fluid absorption and total NHE3 expression were not changed in Lpar5ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5ΔIEC mice, providing direct evidence for the regulatory role of LPA5. NHE3 activation involves trafficking of NHE3 from the terminal web to microvilli, and this mobilization of NHE3 by LPA was abolished in Lpar5ΔIEC mice. Dysregulation of NHE3 was specific to LPA, and insulin and cholera toxin were able to stimulate and inhibit NHE3, respectively, in both wild-type and Lpar5ΔIEC mice. The current study for the first time demonstrates the necessity of LPA5 in LPA-mediated stimulation of NHE3 in vivo. NEW & NOTEWORTHY This study is the first to assess the role of LPA5 in NHE3 regulation and fluid absorption in vivo using a mouse that lacks LPA5 in intestinal epithelial cells, Lpar5ΔIEC. Basal rates of NHE3 activity and fluid absorption, and total NHE3 expression were not changed in Lpar5ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5ΔIEC mice, providing direct evidence for the regulatory role of LPA5.

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