• MeSH
• dextrany aplikace a dávkování   terapeutické užití   MeSH
• hypoxie MeSH
• ionizující záření MeSH
• myši MeSH
• tenké střevo cytologie   účinky záření   MeSH
• viabilita buněk účinky léků   účinky záření   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

• MeSH
• enteritida mortalita   patofyziologie   veterinární   MeSH
• experimentální radiační poranění MeSH
• krysa rodu rattus MeSH
• radiační účinky MeSH
• radiometrie metody   MeSH
• výzkumný projekt statistika a číselné údaje   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

Despite recent progress in recognizing the importance of mesenchymal cells for the homeostasis of the intestinal system, the current picture of how these cells communicate with the associated epithelial layer remains unclear. To describe the relevant cell populations in an unbiased manner, we carried out a single-cell transcriptome analysis of the adult murine colon, producing a high-quality atlas of matched colonic epithelium and mesenchyme. We identify two crypt-associated colonic fibroblast populations that are demarcated by different strengths of platelet-derived growth factor receptor A (Pdgfra) expression. Crypt-bottom fibroblasts (CBFs), close to the intestinal stem cells, express low levels of Pdgfra and secrete canonical Wnt ligands, Wnt potentiators, and bone morphogenetic protein (Bmp) inhibitors. Crypt-top fibroblasts (CTFs) exhibit high Pdgfra levels and secrete noncanonical Wnts and Bmp ligands. While the Pdgfralow cells maintain intestinal stem cell proliferation, the Pdgfrahigh cells induce differentiation of the epithelial cells. Our findings enhance our understanding of the crosstalk between various colonic epithelial cells and their associated mesenchymal signaling hubs along the crypt axis-placing differential Pdgfra expression levels in the spotlight of intestinal fibroblast identity.

• MeSH
• analýza jednotlivých buněk metody   MeSH
• buněčná diferenciace fyziologie   MeSH
• epitelové buňky metabolismus   MeSH
• fibroblasty klasifikace   metabolismus   MeSH
• homeostáza MeSH
• kmenové buňky cytologie   MeSH
• kolon metabolismus   fyziologie   MeSH
• kostní morfogenetické proteiny metabolismus   MeSH
• mezoderm cytologie   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proliferace buněk fyziologie   MeSH
• signální transdukce MeSH
• stanovení celkové genové exprese metody   MeSH
• střeva fyziologie   MeSH
• střevní sliznice metabolismus   MeSH
• transkriptom genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The diagnosis and assessment of the severity of intestinal mucosal damage in cancer patients treated with cytotoxic drugs still rely on anamnestic data. There is cumulative evidence that measurement of intestinal permeability may represent a sensitive indicator of intestinal damage by cytotoxic agents. The intestinal permeability testing is based on differential permeability of tight junctions along the crypt-villus axis to nonmetabolized sugars. Cytotoxic drugs induce flattening of villi, leading to increased exposure of luminal contents to crypts and increased disaccharide absorption. An increased disaccharide/monosaccharide ratio and decreased xylose absorption have been described in patients treated with different cytotoxic drugs across a spectrum of malignant tumors that correlated with clinical manifestations, and were used to monitor the effect of therapeutic interventions. Copyright 2005 S. Karger AG, Basel.

• MeSH
• financování organizované MeSH
• lidé MeSH
• mukozitida diagnóza   chemicky indukované   MeSH
• nádory farmakoterapie   komplikace   MeSH
• nemoci střev diagnóza   chemicky indukované   MeSH
• permeabilita MeSH
• protinádorové látky škodlivé účinky   MeSH
• střevní sliznice imunologie   metabolismus   účinky léků   MeSH
• Check Tag
• lidé MeSH

• MeSH
• intestinální absorpce fyziologie   MeSH
• kolon fyziologie   metabolismus   MeSH
• nahromadění stolice metabolismus   MeSH
• sodíkové kanály fyziologie   MeSH
• střevní sekrety fyziologie   metabolismus   MeSH
• střevní sliznice fyziologie   metabolismus   MeSH
• vodní a elektrolytová rovnováha fyziologie   MeSH
• Publikační typ
• přehledy MeSH

The Wnt pathway plays a crucial role in self-renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N-terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild-type (wt) TCF4 protein decreased transcription of β-catenin-TCF4-responsive genes. Interestingly, suppression of Wnt/β-catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC-specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc-deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell-autonomous inhibition of β-catenin-Tcf-mediated transcription.

• MeSH
• beta-katenin metabolismus   MeSH
• buněčná diferenciace MeSH
• buněčné dělení MeSH
• genetická transkripce MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• proliferace buněk MeSH
• signální dráha Wnt * MeSH
• střevní sliznice cytologie   metabolismus   MeSH
• tenké střevo cytologie   metabolismus   MeSH
• transkripční faktory BHLH-Zip chemie   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by the Apc loss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditional Apc allele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of the Msx1 gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens, MSX1 displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.

• MeSH
• beta-katenin metabolismus   MeSH
• buněčná diferenciace MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• myši knockoutované MeSH
• nádory tračníku genetika   patologie   MeSH
• protein familiární adenomatózní polypózy genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální dráha Wnt MeSH
• stanovení celkové genové exprese MeSH
• střevní sliznice metabolismus   patologie   MeSH
• tenké střevo patologie   MeSH
• transkripční faktor MSX1 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In theONstate, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the HippoOFFstate, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The activity of the Wnt pathway undergoes complex regulation to ensure proper functioning of this principal signaling mechanism during development of adult tissues. The regulation may occur at several levels and includes both positive and negative feedback loops. In the present study we employed one of such negative feedback regulators, naked cuticle homolog 1 (Nkd1), to follow the Wnt pathway activity in the intestine and liver and in neoplasia originated in these organs. Using lineage tracing in transgenic mice we localized Nkd1 mRNA to the bottom parts of the small intestinal crypts and hepatocytes surrounding the central vein of the hepatic lobule. Furthermore, in two mouse models of intestinal tumorigenesis, Nkd1 expression levels were elevated in tumors when compared to healthy tissue. We utilized a collection of human intestinal polyps and carcinomas to confirm that NKD1 represents a robust marker of neoplastic growth. In addition, expression analysis of NKD1 in liver cancer showed that high expression levels of the gene distinguish a subclass of hepatocellular carcinomas related to aberrant Wnt signaling. Finally, our results were confirmed by bioinformatic analysis of large publicly available datasets that included gene expression profiling and high-throughput sequencing data of human colon and liver cancer specimens.

• MeSH
• beta-katenin genetika   metabolismus   MeSH
• genetická transkripce MeSH
• hepatocelulární karcinom metabolismus   patologie   MeSH
• hepatocyty metabolismus   patologie   MeSH
• kolorektální nádory metabolismus   patologie   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mutace MeSH
• myši transgenní MeSH
• myši MeSH
• nádory jater metabolismus   patologie   MeSH
• protein familiární adenomatózní polypózy nedostatek   genetika   metabolismus   MeSH
• proteiny Wnt metabolismus   MeSH
• signální transdukce MeSH
• střevní nádory metabolismus   patologie   MeSH
• transportní proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Zearalenone (ZEA) as an estrogen-like mycotoxin can cause the inflammatory injury of the cecum. How to reduce the harm that ZEA causes to humans and animals is a current concern for researchers. In this study, we aimed to ascertain whether Bacillus velezensis A2 (A2) could alleviate injury caused by ZEA by regulating the intestinal flora and the content of short chain fatty acids in the cecum among mice. Our results showed that Bacillus velezensis A2 improved the fold height, myometrial thickness, and crypt depth of the cecum induced by ZEA. Enzyme-linked immunosorbent assay and Western blotting results showed that A2 could decrease the ZEA-induced increase in expression levels of IL-2, IL-6, IFN-γ, TNF-α, and FC. Studies also showed that A2 increased the content of SCFA in the cecum which was decreased by ZEA. The microbial communities in the cecum were changed when given ZEA or A2. A2 was found to greatly reduce the ZEN-induced increase in the relative abundance of p_Actinobacteria, p_Protebacteria, o_Coriobacteriales, g_Anaerotruncus, g_Pseudoflavonifractor, g_Lachnoclostridium, g_Enterorhabdus, and f_Oscillospiraceae, and increase the ZEN-induced decrease in the relative abundance of f_Coriobacteriales. Results indicated that Bacillus velezensis A2 can largely ameliorate the intestinal inflammatory injury induced by ZEA in mice by regulating the microflora and short chain fatty acids content.

• Publikační typ
• časopisecké články MeSH