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The Role of Intestinal Epithelial Cells and Their Cellular Interactions

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 March 2025 | Viewed by 9890

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Dr. Younggeon Jin

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Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA
Interests: mucosal barrier, tight and adherens junctions, intestinal stem cells, mesenchymal stromal cells, and postnatal intestinal development

Special Issue Information

Dear Colleagues,

This Special Issue, “The Role of Intestinal Epithelial Cells and their Cellular Interactions”, will mainly focus on the role of intestinal epithelial cells (IECs) and their regulation and crosstalk with stromal and immune cells.

The intestinal mucosal barrier represents the largest interface between the luminal contents and the body's internal milieu. Single-layered IECs are a semipermeable barrier that allows the absorption of nutrients and transport of substances and prevents the entry of harmful substances, luminal antigens, and pathogens. Due to the harsh luminal environment, IECs possess a great capacity for self-renewal to maintain organ homeostasis and promote regeneration, which is fueled by a population of intestinal stem cells. The IECs dynamically interact with both intestinal stromal and immune cells to maintain tissue homeostasis and alterations to pathological conditions. Understanding the impact of IECs and their interaction with subepithelial cells is essential for improving gut health.

We cordially invite authors to submit original research or review articles pertaining to this important and fast-progressing field of biomedicine. Potential topics include, but are not limited to:

The mucosal barrier in gastrointestinal physiology and pathology;
Intestinal stem cell biology in tissue homeostasis and regeneration;
The crosstalk of intestinal epithelial cells with stromal or immune cells.

Dr. Younggeon Jin
Guest Editor

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Keywords

intestinal epithelial barrier
tight junctions
intestinal stem cells
mesenchymal stromal cells
immune cells

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Published Papers (6 papers)

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16 pages, 3981 KiB

Open AccessArticle

Integration of Stromal Cells and Hydrogel Below Epithelium Results in Optimal Barrier Properties of Small Intestine Organoid Models

by Melis Asal, Maria Thon, Taco Waaijman, Hetty J. Bontkes, Sandra J. van Vliet, Reina E. Mebius and Susan Gibbs

Biomedicines 2024, 12(12), 2913; https://doi.org/10.3390/biomedicines12122913 - 21 Dec 2024

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Abstract

Background/Objectives: The barrier properties of the human small intestine play a crucial role in regulating digestion, nutrient absorption and drug metabolism. Current in vitro organotypic models consist only of an epithelium, which does not take into account the possible role of stromal cells such as fibroblasts or the extracellular matrix (ECM) which could contribute to epithelial barrier properties. Therefore, the aim of this study was to determine whether these stromal cells or ECM were beneficial or detrimental to barrier function when incorporated into an organotypic human small intestine model. Methods: Intestinal epithelial cell lines or primary cell organoids derived from the epithelial stem cells of the small intestine were cultivated either on a porous Transwell membrane (epithelial model) or on a primary small intestinal stromal cell-populated collagen-fibrin hydrogel (full thickness model). Results: Both models expressed villin (enterocytes), lysozyme (Paneth cells), Ki67 (proliferative cells) and zonula occludens-1 (tight junctions). The polarized epithelial barriers of the full thickness models demonstrated a significant decrease in transepithelial electrical resistance (TEER) with values comparable to that found in the native small intestine in contrast to the higher TEER values observed in the epithelial models. This correlated to an increase in secreted zonulin, a regulator of intestine permeability, in the full thickness models. The decreased TEER values were due to both the stromal cells and the choice of the hydrogel versus the Transwell membrane. Moreover, erythropoietin and epithelial growth factor secretion, which have roles in regulating barrier integrity, directly correlated with the changes in TEER and permeability. Conclusions: This study emphasizes the importance of different cell types being incorporated into small intestine models and, also, the influence of the scaffold or matrix used. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

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Figure 1

Figure 1
Experimental design of the small intestine models. (a) Schematic representation of the models. Epithelium (EPI) model: epithelial cells (either from cell lines or primary organoids) grown on Matrigel® coated Transwell inserts; Full thickness (FT) model: epithelial cells (either from cell lines or primary organoids) grown on a stromal cell-populated collagen-fibrin based hydrogel. M1: Epithelial medium; M2: Stromal cell medium. (b) Schematic representation of the cell sources and isolation procedures used to construct the two intestinal models described in (a). Created in BioRender. Full article ">Figure 2
Histology and expression of intestine-specific markers of the developed small intestine epithelium (EPI) and full thickness (FT) models: (a) histology (H&E) and (b) IF staining of the enterocyte marker villin (VIL; green), the Paneth cell marker lysozyme (LYZ; green), the transient amplifying cell marker (Ki67; green), and tight junction marker zonula occludens-1 (ZO-1; green) in the native small intestine epithelium, EPI, and FT models. Nuclei are stained blue with DAPI. Representative pictures of 3 independent experiments, each with an intra experimental replicate, are shown. Scale bar = 50 μm. Full article ">Figure 3
Assessment of the barrier properties of EPI and FT models. (a) TEER measurements and secreted zonulin quantification of cell line and organoid models to assess barrier properties and permeability, respectively. (b) Quantification of the intestinal barrier property-related growth factors EPO and EGF in culture supernatants from the basolateral compartment of the models. n = 3 independent experiments (represented with triangle, square, circle symbols), each with 2 intra experimental replicates. The data are shown as mean ± SEM; unpaired t-test; * = p < 0.05; ** = p < 0.01; *** = p < 0.001. EPI: Epithelial model; FT: Full thickness model. Full article ">Figure 4
Hydrogel and secretome differentially influence intestinal barrier properties. (a) Schematic representation of the various models used to test the effect of secretome and the hydrogel. M1: epithelial medium; M2: stromal cell medium; secretome: conditioned medium collected from stromal cells grown as monolayers. Created in BioRender. (b) TEER measurement of the models to assess their barrier properties. The dashed lines represent the physiological TEER range. n = 3 independent experiments (represented with triangle, square, circle symbols) for cell lines, n = 4 (represented with upward/downward triangle, square, circle symbols)for organoid paracrine models, each with an intra-experimental replicate. Symbols represent the different experiments. The data are shown as mean ± SEM; one-way ANOVA. * = p < 0.05; ** = p < 0.01; *** = p < 0.001. Full article ">Figure 5
Growth factor secretion by intestine models. (a) Schematic representation of the different experimental conditions. Created in BioRender. (b) Quantification of secreted hepatocyte growth factor (HGF), stem cell factor (SCF), angiopoietin-2 (Ang2), vascular endothelial growth factor (VEGF), and M-CSF in the supernatants of the different models. Culture medium was refreshed 24 h prior to harvesting the models and collecting the conditioned supernatants. EPI: Epithelial model, FT: Full thickness model and LP: Stromal layer cells within the hydrogel without the epithelium (with either cell line medium or organoid medium in the apical compartment). The data from n = 3 independent experiments (represented with triangle, square, circle symbols), each with an intra-experimental replicate, are shown as mean ± SEM. One-way ANOVA. * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. Full article ">Figure 6
Chemokine secretion by intestine models. The culture medium was refreshed 24 h prior to harvesting the models and collecting the conditioned supernatants. EPI: epithelial model; FT: full thickness model; and LP: stromal cell hydrogel without the epithelium. The data from n = 3 independent experiments (represented with triangle, square, circle symbols), each with an intra-experimental replicate, are shown as mean ± SEM. One-way ANOVA. * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001. Full article ">

12 pages, 1222 KiB

Open AccessArticle

Hyperosmotic Stress Induces the Expression of Organic Osmolyte Transporters in Porcine Intestinal Cells and Betaine Exerts a Protective Effect on the Barrier Function

by Elena De Angelis, Paolo Borghetti, Benedetta Passeri, Valeria Cavalli, Luca Ferrari, Melania Andrani, Paolo Martelli and Roberta Saleri

Biomedicines 2024, 12(10), 2391; https://doi.org/10.3390/biomedicines12102391 - 18 Oct 2024

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Abstract

Background/objectives: The porcine intestinal epithelium plays a fundamental role as a defence interface against pathogens. Its alteration can cause severe inflammatory conditions and diseases. Hyperosmotic stress under physiological conditions and upon pathogen challenge can cause malabsorption. Different cell types counteract the osmolarity increase by accumulating organic osmolytes such as betaine, taurine, and myo-inositol through specific transporters. Betaine is known for protecting cells from hyperosmotic stress and has positive effects when fed to pigs. The aim of this study is to demonstrate the modulation of osmolyte transporters gene expression in IPEC-J2 during osmolarity changes and assess the effects of betaine. Methods: IPEC-J2 were seeded in transwells, where differentiate as a polarized monolayer. Epithelial cell integrity (TEER), oxidative stress (NO) and gene expression of osmolyte transporters, tight junction proteins (TJp) and pro-inflammatory cytokines were evaluated. Results: Cells treated with NaCl hyperosmolar medium (500 mOsm/L) showed a TEER decrease at 3 h and detachment within 24 h, associated with an osmolyte transporters reduction. IPEC-J2 treated with mannitol hyperosmolar medium (500 mOsm/L) upregulated taurine (TauT), myo-inositol (SMIT) and betaine (BGT1) transporters expression. A decrease in TJp expression was associated with a TEER decrease and an increase in TNFα, IL6, and IL8. Betaine could attenuate the hyperosmolarity-induced reduction in TEER and TJp expression, the NO increase and cytokines upregulation. Conclusions: This study demonstrates the expression of osmolyte transporters in IPEC-J2, which was upregulated upon hyperosmotic treatment. Betaine counteracts changes in intracellular osmolarity by contributing to maintaining the epithelial barrier function and reducing the inflammatory condition. Compatible osmolytes may provide beneficial effects in therapies for diseases characterized by inflammation and TJp-related dysfunctions. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

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20 pages, 1213 KiB

Open AccessReview

Overview of the Trending Enteric Viruses and Their Pathogenesis in Intestinal Epithelial Cell Infection

by Chi-Chong Chio, Jou-Chun Chien, Hio-Wai Chan and Hsing-I Huang

Biomedicines 2024, 12(12), 2773; https://doi.org/10.3390/biomedicines12122773 - 5 Dec 2024

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Abstract

Enteric virus infection is a major public health issue worldwide. Enteric viruses have become epidemic infectious diseases in several countries. Enteric viruses primarily infect the gastrointestinal tract and complete their life cycle in intestinal epithelial cells. These viruses are transmitted via the fecal–oral route through contaminated food, water, or person to person and cause similar common symptoms, including vomiting, abdominal pain, and diarrhea. Diarrheal disease is the third leading cause of death in children under five years of age, accounting for approximately 1.7 billion cases and 443,832 deaths annually in this age group. Additionally, some enteric viruses can invade other tissues, leading to severe conditions and even death. The pathogenic mechanisms of enteric viruses are also unclear. In this review, we organized the research on trending enteric virus infections, including rotavirus, norovirus, adenovirus, Enterovirus-A71, Coxsackievirus A6, and Echovirus 11. Furthermore, we discuss the gastrointestinal effects and pathogenic mechanisms of SARS-CoV-2 in intestinal epithelial cells, given the gastrointestinal symptoms observed during the COVID-19 pandemic. We conducted a literature review on their pathogenic mechanisms, which serves as a guide for formulating future treatment strategies for enteric virus infections. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

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Full article ">Figure 1
The mechanism of RV pathogenesis. RV produces NSP4 while infecting IECs. This protein promotes the transportation of Ca2+ from the ER to the cytoplasm, which causes Ca2+-dependent diarrhea. NSP4 can be secreted extracellularly, where it stimulates the expression of PLC in uninfected cells, increasing the production of IP3. This causes further release of Ca2+ from the ER into the cytoplasm. The resulting increase in cytoplasmic Ca2+ concentration disrupts tight junction integrity, leading to water influx into the intestinal lumen. Additionally, elevated cytoplasmic Ca2+ induces the secretion of 5-HT, which stimulates the myenteric plexus, enhancing intestinal motility. The stimulated myenteric plexus further activates the submucosal plexus to release VIP, increasing cAMP production in IECs. This leads to the secretion of NaCl and water into the intestinal lumen, ultimately causing diarrhea. RV, rotavirus; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; 5-HT, 5-hydroxytryptamine; and VIP, vasoactive intestinal peptide. Full article ">Figure 2
The potential route of EV-A71 invades the central neuron system. EV-A71 primarily infects and replicates in IECs. The generated EV-A71 exits from host cells by lytic and non-lytic processes and then invades the CNS via several potential pathways: (1) Retrograde axon transport: EV-A71 infects muscle cells and then enters spinal motor nerves, traveling retrogradely along axons to the CNS. (2) Crossing the BBB: EV-A71 circulates in the bloodstream and directly crosses the BBB to invade the CNS. (3) Trojan horse invasion: EV-A71 infects immune cells, which serve as carriers to transport the virus across the BBB into the CNS. (4) Utilize exosome transport: EV-A71 may be packaged within exosomes, which facilitate its crossing of the BBB and subsequent infection of neural cells. blood–brain barrier; EV-A71, Enterovirus A71; IECs, intestinal epithelial cells. Full article ">

18 pages, 3903 KiB

Open AccessReview

Crosstalk Within the Intestinal Epithelium: Aspects of Intestinal Absorption, Homeostasis, and Immunity

by Liang-En Yu, Wen-Chin Yang and Yu-Chaun Liang

Biomedicines 2024, 12(12), 2771; https://doi.org/10.3390/biomedicines12122771 - 5 Dec 2024

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Abstract

Gut health is crucial in many ways, such as in improving human health in general and enhancing production in agricultural animals. To maximize the effect of a healthy gastrointestinal tract (GIT), an understanding of the regulation of intestinal functions is needed. Proper intestinal functions depend on the activity, composition, and behavior of intestinal epithelial cells (IECs). There are various types of IECs, including enterocytes, Paneth cells, enteroendocrine cells (EECs), goblet cells, tuft cells, M cells, and intestinal epithelial stem cells (IESCs), each with unique 3D structures and IEC distributions. Although the communication between IECs and other cell types, such as immune cells and neurons, has been intensively reviewed, communication between different IECs has rarely been addressed. The present paper overviews the networks among IECs that influence intestinal functions. Intestinal absorption is regulated by incretins derived from EECs that induce nutrient transporter activity in enterocytes. EECs, Paneth cells, tuft cells, and enterocytes release signals to activate Notch signaling, which modulates IESC activity and intestinal homeostasis, including proliferation and differentiation. Intestinal immunity can be altered via EECs, goblet cells, tuft cells, and cytokines derived from IECs. Finally, tools for investigating IEC communication have been discussed, including the novel 3D intestinal cell model utilizing enteroids that can be considered a powerful tool for IEC communication research. Overall, the importance of IEC communication, especially EECs and Paneth cells, which cover most intestinal functional regulating pathways, are overviewed in this paper. Such a compilation will be helpful in developing strategies for maintaining gut health. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

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Figure 1

Figure 1
Intestinal glucose absorption is regulated via the communication between EEC-derived incretins and enterocytes. 5-HT, serotonin; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; CCKR, cholecystokinin receptor; EC cells, enterochromaffin cells; GIP, gastric inhibitory peptide; GIPR, gastric inhibitory peptide receptor; GLP2, glucagon-like peptide 2; GLP2R, glucagon-like peptide 2 receptor; GLUT2, glucose transporter 2; GPCRs, G protein-coupled receptors; SERT, serotonin transporter; SGLT1, sodium glucose co-transporter 1; T1R1/T1R3, taste receptor type 1 member 2/taste receptor type 1 member 3. ↑, increase. Full article ">Figure 2
Intestinal amino acid, peptide, fatty acid, and lipid absorption are regulated via the communication between EEC-derived incretins and enterocytes. cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; CCKR, cholecystokinin receptor; CD36, cluster of differentiation 36; GIP, gastric inhibitory peptide; GIPR, gastric inhibitory peptide receptor; GLP2, glucagon-like peptide 2; GLP2R, glucagon-like peptide 2 receptor; GPCRs, G protein-coupled receptors; LCFA, long-chain fatty acid; mTORC1, mammalian target of rapamycin complex 1; PepT1, intestinal peptide transporter 1; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B. ↑, increase. Full article ">Figure 3
IESC activity, including proliferation, differentiation, and maintenance, is regulated via the communication between EECs, Paneth cells, enterocytes, and IESCs. Dll1/4, delta-like canonical Notch ligand 1/4; EECs, enteroendocrine cells; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GLP2, glucagon-like peptide 2; GLP2R, glucagon-like peptide 2 receptor; HK2, hexokinase 2; IESCs, intestinal epithelial stem cells; LGRs, leucine-rich repeat containing G protein-coupled receptors; p38, p38 mitogen-activated protein kinase; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; ROS, reactive oxygen species. ↑, increase; ↓, decrease. Full article ">

19 pages, 1513 KiB

Open AccessReview

Subepithelial Stromal Cells: Their Roles and Interactions with Intestinal Epithelial Cells during Gut Mucosal Homeostasis and Regeneration

by Hammed Ayansola, Edith J. Mayorga and Younggeon Jin

Biomedicines 2024, 12(3), 668; https://doi.org/10.3390/biomedicines12030668 - 17 Mar 2024

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Abstract

Intestinal epithelial cell activities during homeostasis and regeneration are well described, but their potential interactions with stromal cells remain unresolved. Exploring the functions of these heterogeneous intestinal mesenchymal stromal cells (iMSCs) remains challenging. This difficulty is due to the lack of specific markers for most functionally homogenous subpopulations. In recent years, however, novel clustering techniques such as single-cell RNA sequencing (scRNA-seq), fluorescence-activated cell sorting (FACS), confocal microscope, and computational remodeling of intestinal anatomy have helped identify and characterize some specific iMSC subsets. These methods help researchers learn more about the localization and functions of iMSC populations during intestinal morphogenic and homeostatic conditions. Consequently, it is imperative to understand the cellular pathways that regulate their activation and how they interact with surrounding cellular components, particularly during intestinal epithelial regeneration after mucosal injury. This review provides insights into the spatial distribution and functions of identified iMSC subtypes. It focuses on their involvement in intestinal morphogenesis, homeostasis, and regeneration. We reviewed related signaling mechanisms implicated during epithelial and subepithelial stromal cell crosstalk. Future research should focus on elucidating the molecular intermediates of these regulatory pathways to open a new frontier for potential therapeutic targets that can alleviate intestinal mucosa-related injuries. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

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Figure 1
Multiple signaling pathways regulating intestinal epithelial–mesenchymal crosstalk in the crypt. The diagram provides an overview of the intricate mechanisms involved in the interactions between crypt-based epithelial cells and the neighboring iMSCs. This interplay controls intestinal stem cell (ISC) homeostasis and epithelial differentiation. The activation of Wnt-promoting pathways and inhibition of Bmp/Bmpr binding orchestrate ISC stemness in the crypt base. Paneth cells secrete Wnt, Notch, and EGF ligands that induce Wnt target gene transcription in ISC. Wnt ligands secreted by subcryptal iMSCs bind FZD and LRPs co-receptors. The ligand–receptor binding stabilized β-catenin in the Wnt signaling cascade to promote ISC-related gene transcription. Rspos binding LGR family receptors stabilized FZD expressions, contributing to WNT pathway activation. In addition, subcryptal iMSCs secrete Bmp antagonists such as Gremlin to maintain Wnt activities in the ISC niche. Full article ">Figure 2
Intestinal villus base epithelial-secreted ligands activate hedgehog signaling in neighboring mesenchymal cells. These epithelial–mesenchymal interactions at the villus base stimulate intestinal epithelial cell terminal differentiation and coordinate the migration of differentiated cells toward the villus tip. Hedgehog ligands produced by epithelial cells bind on the Pitch1 receptor of PDGFRαhi cells located at the villus base. This binding triggers the transcription of hedgehog target genes. The genes transcribed by the Gli family of PDGFRαhi cells include Bmps. Secreted Bmp ligands from these iMSCs bind with the Bmp receptor (Bmpr) on adjacent epithelial cells. The Bmp and Bmpr binding subsequently phosphorylate the Smad family transcription factor, which in turn induces the differentiation of villus epithelial cells. Full article ">Figure 3
Schematic representation of intestinal mesenchymal stromal cell subsets and their location. The illustration here describes the subpopulations of PDGFRα-expressing cells, including telocytes, CD81− cells, and trophocytes. The trophocyte cluster group, CD81+, is confined to the subcryptal domain, beneath the muscularis mucosa, to secrete Wnt-promoting factors that support the ISC niche. Other PDGFRαlo subsets, including CD55hi and Fgfr2+ cells, localize in the lamina propria and extend upward to the TA domain/villi trunk to initiate terminal differentiation. They switch the signal gradients from Wnt-promoting factors to Bmp agonists. PDGFRαhi subsets form the subepithelial stromal populations that are localized in the villi core in the small intestine and the colon top [<a href="#B38-biomedicines-12-00668" class="html-bibr">38</a>,<a href="#B39-biomedicines-12-00668" class="html-bibr">39</a>]. Full article ">

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8 pages, 2520 KiB

Open AccessBrief Report

Colitis Is Associated with Loss of the Histidine Phosphatase LHPP and Upregulation of Histidine Phosphorylation in Intestinal Epithelial Cells

by Markus Linder, Dritan Liko, Venkatesh Kancherla, Salvatore Piscuoglio and Michael N. Hall

Biomedicines 2023, 11(8), 2158; https://doi.org/10.3390/biomedicines11082158 - 1 Aug 2023

Cited by 6 | Viewed by 1716

Abstract

Protein histidine phosphorylation (pHis) is a posttranslational modification involved in cell cycle regulation, ion channel activity and phagocytosis. Using novel monoclonal antibodies to detect pHis, we previously reported that the loss of the histidine phosphatase LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) results in elevated pHis levels in hepatocellular carcinoma. Here, we show that intestinal inflammation correlates with the loss of LHPP in dextran sulfate sodium (DSS)-treated mice and in inflammatory bowel disease (IBD) patients. Increased histidine phosphorylation was observed in intestinal epithelial cells (IECs), as determined by pHis immunofluorescence staining of colon samples from a colitis mouse model. However, the ablation of Lhpp did not cause increased pHis or promote intestinal inflammation under physiological conditions or after DSS treatment. Our observations suggest that increased histidine phosphorylation plays a role in colitis, but the loss of LHPP is not sufficient to increase pHis or to cause inflammation in the intestine. Full article

(This article belongs to the Special Issue The Role of Intestinal Epithelial Cells and Their Cellular Interactions)

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Figure 1
Intestinal inflammation correlates with downregulation of LHPP and increased histidine phosphorylation. (A) Analysis of a publicly available dataset comparing the mRNA expression of known histidine phosphatases (LHPP, PGAM5, PHPT1) and histidine kinases (NME1, NME2) in colon tissue from healthy patients (CTRL) with that of patients suffering from ulcerative colitis (UC) and Crohn’s disease (CD). (B) Bodyweight and colon length of mice treated (DSS, n = 4) and untreated (CTRL, n = 3) with DSS at the indicated timepoints (days). (C) Immunoblot analysis of histidine phosphatases and kinases in colon lysates of DSS-treated and untreated mice at the indicated timepoints (n = 3). (D) Quantification of LHPP protein levels normalized to calnexin at different timepoints of the DSS treatment (n = 3). (E) Immunohistochemistry visualization of LHPP in the colon samples of mice treated (DSS) and untreated (CTRL) for 7 days with DSS. Scale bar: 100 μm. (F–H) Immunoblot analysis of 1- and 3-pHis levels in colon samples from DSS-treated (DSS, n = 3−4) and untreated (CTRL, n= 3) mice at the indicated timepoints. (I) Quantification of the 1− and 3−pHis levels in (H). (J) DAPI and immunofluorescence staining of colon samples from untreated mice (CTRL) and mice treated with DSS for 7 days. Scale bars: 50 μm (low magnification) and 10 μm (high magnification). Data are shown as the mean ± SEM; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.001; ns = not significant. Full article ">Figure 2
LHPP is dispensable for the development of colitis. (A) IHC (LHPP, Ki67, cleaved caspase 3) and H&E staining of colon samples of 1.5-year-old Lhpp+/+ and Lhpp−/− mice. Red arrowheads indicate cleaved (cl.) caspase 3−positive cells. Scale bars: 100 μm. (B) Immunoblot analysis of 1− and 3−pHis and histidine phosphatase protein levels in colon samples from Lhpp+/+ (n = 3) and Lhpp−/− (n = 4) mice. (C) Quantification of the 1− and 3−pHis levels in B. (D) Immunoblot analysis of NME1, NME2 and LHPP in colon samples from Lhpp+/+ (n = 3) and Lhpp−/− (n = 4) mice. (E) Bodyweight during DSS treatment (n = 3 for untreated animals; n = 6 for DSS-treated animals). (F) Colon length and spleen weight of the control animals (n = 3) or after 7 days DSS treatment (n = 6). (G) Immunoblot analysis of 1− and 3−pHis and LHPP protein levels in colon samples from Lhpp+/+ (n = 2) and Lhpp−/− (n = 3) mice treated with DSS for 7 days. (H) Quantification of the 1− and 3−pHis levels in (G) with n = 6. (I) Immunoblot analysis of histidine phosphatases and kinases in the colon samples from Lhpp+/+ and Lhpp−/− mice treated with DSS for 7 days (n = 6). Data are shown as the mean ± SEM; *, p < 0.05; ****, p < 0.001. Full article ">

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