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Frontiers in Immunology 2023Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine... (Review)
Review
Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn's disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.
Topics: Humans; Paneth Cells; Acute Disease; Pancreatitis; COVID-19; Intestines
PubMed: 36993974
DOI: 10.3389/fimmu.2023.1115552 -
Stem Cell Research & Therapy Aug 2020Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies... (Review)
Review
Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.
Topics: Cell Differentiation; Intestines; Paneth Cells; Signal Transduction; Stem Cells
PubMed: 32787930
DOI: 10.1186/s13287-020-01857-7 -
Current Opinion in Gastroenterology Nov 2022Paneth cells are specialized, secretory epithelial cells located in the small intestine. Although their existence was first described in 1872, their precise role in the... (Review)
Review
PURPOSE OF REVIEW
Paneth cells are specialized, secretory epithelial cells located in the small intestine. Although their existence was first described in 1872, their precise role in the gut remained unclear for over a century. Over the past few decades, elegant studies have shown Paneth cells play a key role enhancing gut barrier function, as niche cells for the intestinal stem cell compartment and via secreting antimicrobial peptides to establish an antimicrobial barrier at the epithelial surface. This review describes what is known about Paneth cell biology from human and animal studies with a focus on their putative role in clinical gastrointestinal disease.
RECENT FINDINGS
Recent work has demonstrated important associations of dysfunctional Paneth cells with several gastrointestinal disorders. These include Crohn's disease, enteric infections, graft-versus-host disease, necrotizing enterocolitis, and environmental enteric dysfunction. Ongoing studies are examining precisely how Paneth cell biology is altered in these various disease states.
SUMMARY
By understanding the mechanisms of Paneth cell regulation - and how these processes go awry in specific gastrointestinal diseases - we set the stage for using Paneth cells as biomarkers for disease progression and developing novel therapeutics that augment Paneth cell function to treat a spectrum of gastrointestinal disorders.
Topics: Animals; Crohn Disease; Humans; Infant, Newborn; Intestine, Small; Paneth Cells
PubMed: 36165037
DOI: 10.1097/MOG.0000000000000887 -
Cellular and Molecular Gastroenterology... 2022The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within...
Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn's Disease Patients.
BACKGROUND & AIMS
The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn's disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type-specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non-inflammatory bowel disease control patients.
METHODS
Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non-inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types.
RESULTS
Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type-specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type-specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes.
CONCLUSIONS
Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD.
Topics: Adult; Crohn Disease; DNA Transposable Elements; Epithelium; Genome-Wide Association Study; Humans; Paneth Cells; Single-Cell Analysis
PubMed: 35158099
DOI: 10.1016/j.jcmgh.2022.02.005 -
Gut Microbes Dec 2023Classically, Axin1 is considered a regulator of Wnt/β-catenin signaling. However, Axin1's roles in host-microbial interactions have been unknown. Our recent study has...
Classically, Axin1 is considered a regulator of Wnt/β-catenin signaling. However, Axin1's roles in host-microbial interactions have been unknown. Our recent study has demonstrated that deletion of intestinal epithelial Axin1 in epithelial cells and Paneth cells protects the host against colitis by enhancing . Loss of intestinal epithelial or Paneth cell Axin1 results in increased Wnt/β-catenin signaling, proliferation, and cell migration. This is associated with morphologically altered goblet and Paneth cells, including increased Muc2 and decreased lysozyme. Axin1 deletion specifically enriched . in Axin1 knockout mice is the driver of protection against DSS-induced inflammation. Here, we feature several significant conceptual changes, such as differences between Axin1 and Axin2, Axin1 in innate immunity and microbial homeostasis, and Axin1 reduction of . We discuss an important trend in the field related to Paneth cells and tissue-specific Axin1 manipulation of microbiome in health and inflammation.
Topics: Animals; Mice; Axin Protein; beta Catenin; Colitis; Gastrointestinal Microbiome; Inflammation; Microbiota; Paneth Cells
PubMed: 38010886
DOI: 10.1080/19490976.2023.2286674 -
Cell Proliferation Jan 2021Paneth cells (PCs) are located at the base of small intestinal crypts and secrete the α-defensins, human α-defensin 5 (HD-5) and human α-defensin 6 (HD-6) in response... (Review)
Review
Paneth cells (PCs) are located at the base of small intestinal crypts and secrete the α-defensins, human α-defensin 5 (HD-5) and human α-defensin 6 (HD-6) in response to bacterial, cholinergic and other stimuli. The α-defensins are broad-spectrum microbicides that play critical roles in controlling gut microbiota and maintaining intestinal homeostasis. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease (CD), is a complicated autoimmune disorder. The pathogenesis of CD involves genetic factors, environmental factors and microflora. Surprisingly, with regard to genetic factors, many susceptible genes and pathogenic pathways of CD, including nucleotide-binding oligomerization domain 2 (NOD2), autophagy-related 16-like 1 (ATG16L1), immunity-related guanosine triphosphatase family M (IRGM), wingless-related integration site (Wnt), leucine-rich repeat kinase 2 (LRRK2), histone deacetylases (HDACs), caspase-8 (Casp8) and X-box-binding protein-1 (XBP1), are relevant to PCs. As the underlying mechanisms are being unravelled, PCs are identified as the central element of CD pathogenesis, integrating factors among microbiota, intestinal epithelial barrier dysfunction and the immune system. In the present review, we demonstrate how these genes and pathways regulate CD pathogenesis via their action on PCs and what treatment modalities can be applied to deal with these PC-mediated pathogenic processes.
Topics: Animals; Crohn Disease; Humans; Paneth Cells
PubMed: 33174662
DOI: 10.1111/cpr.12958 -
European Journal of Cell Biology 2022Calorie restriction has been recently shown to increase intestinal stem cell competition and to reduce mutation fixation in young mice. However, the impact of aging on...
Calorie restriction has been recently shown to increase intestinal stem cell competition and to reduce mutation fixation in young mice. However, the impact of aging on this process is unknown. By employing Confetti reporter mice, here we show that, unexpectedly, old mice have more intestinal stem cell (ISC) competition than young mice. Moreover, differently from what observed in young mice, calorie restriction, when applied at late-life, decreases this process. Importantly, we also observed a strong correlation between the ISC competition and Paneth cell number. In vivo analysis and in vitro organoid experiments indicated that Paneth cells play a major role in driving intestinal stem cell competition and crypt clonality. Taken together, our results provide evidence that increasing the number of Paneth cells can increase the number of competitive ISCs, representing a valuable therapeutic target to delay fixation of mutated intestinal stem cells.
Topics: Mice; Animals; Paneth Cells; Caloric Restriction; Cell Competition; Intestines; Stem Cells; Intestinal Mucosa
PubMed: 36395573
DOI: 10.1016/j.ejcb.2022.151282 -
Gut Microbes 2022Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to...
Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4pvillin mice were highly resistance to Typhimurium (.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPARγ after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. / (F/B) ratio in FABP4pvillin mice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases.: FABP4: Fatty acid binding protein 4; S. T: Salmonella Typhimurium; HFD: High-fat diet; Defa: α-defensin; 930 HD5: Human α-defensin 5; HD6: Human α-defensin 6; F/B: Firmicutes/Bacteroidetes; SFB: Segmental filamentous bacteria; AMPs: Antimicrobial peptides; PPARγ: Peroxisome proliferator-activated receptor γ; P-PPAR: Phosphorylated PPAR; Dhx15: DEAD-box helicase 15; 935 EGF: Epidermal growth factor; ENR: Noggin and R-spondin 1; CFU: Colony forming unit; Lyz1: Lysozyme 1; Saa1: Serum amyoid A 1; Pla2g2a: Phospholipase A2, group IIA; MMP-7: Matrix metalloproteinase; AU-PAGE: Acid-urea polyacrylamide gel electrophoresis; PA: Palmitic 940 acid; GPR40: G-protein-coupled receptor; GF: Germ-free; EGF: Epidermal growth factor; LP: Lamina propria; KO: Knock out; WT: Wild-type.
Topics: Animals; Humans; Mice; Anti-Infective Agents; Fatty Acid-Binding Proteins; Gastrointestinal Microbiome; Paneth Cells; RNA Helicases
PubMed: 36519446
DOI: 10.1080/19490976.2022.2139978 -
Journal of Proteome Research Oct 2022Paneth cells are antimicrobial peptide-secreting cells located at the base of the crypts of the small intestine. The proteome of Paneth cells is not well defined because...
Paneth cells are antimicrobial peptide-secreting cells located at the base of the crypts of the small intestine. The proteome of Paneth cells is not well defined because of their coexistence with stem cells, making it difficult to culture Paneth cells alone . Using a simplified toluidine blue O method for staining mouse intestinal tissue, laser capture microdissection (LCM) to isolate cells from the crypt region, and surfactant-assisted one-pot protein digestion, we identified more than 1300 proteins from crypts equivalent to 18,000 cells. Compared with the proteomes of villi and smooth muscle regions, the crypt proteome is highly enriched in defensins, lysozymes, and other antimicrobial peptides that are characteristic of Paneth cells. The sensitivity of the LCM-based proteomics approach was also assessed using a smaller number of cell equivalent tissues: a comparable proteomic coverage can be achieved with 3600 cells. This work is the first proteomics study of intestinal tissue enriched with Paneth cells. The simplified workflow enables profiling of Paneth cell-associated pathological changes at the proteome level directly from frozen intestinal tissue. It may also be useful for proteomics studies of other spatially resolved cell types from other tissues.
Topics: Animals; Defensins; Laser Capture Microdissection; Mice; Paneth Cells; Proteome; Proteomics; Surface-Active Agents; Tolonium Chloride
PubMed: 36153828
DOI: 10.1021/acs.jproteome.2c00311 -
Cell Reports Sep 2023Lipolysis-stimulated lipoprotein receptor (LSR) is a multi-functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and...
Lipolysis-stimulated lipoprotein receptor (LSR) is a multi-functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and hepatic clearance of lipoproteins. Here, we investigated whether LSR contributes to intestinal epithelium homeostasis and pathogenesis of intestinal disease. By using multiple conditional deletion mouse models and ex vivo cultured organoids, we find that LSR elimination in intestinal stem cells results in the disappearance of Paneth cells without affecting the differentiation of other cell lineages. Mechanistic studies reveal that LSR deficiency increases abundance of YAP by modulating its phosphorylation and proteasomal degradation. Using gain- and loss-of-function studies, we show that LSR protects against necrotizing enterocolitis through enhancement of Paneth cell differentiation in small-intestinal epithelium. Thus, this study identifies LSR as an upstream negative regulator of YAP activity, an essential factor for Paneth cell differentiation, and a potential therapeutic target for necrotizing enterocolitis.
Topics: Mice; Animals; Paneth Cells; Receptors, Lipoprotein; Enterocolitis, Necrotizing; Cell Differentiation; Intestines; Intestinal Mucosa
PubMed: 37703178
DOI: 10.1016/j.celrep.2023.113118