Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242410 | GEO | 2023/09/08
REPOSITORIES: GEO
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Project description:Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the Phb1 mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.
| S-EPMC10494932 | biostudies-literature
Project description:Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity
| PRJNA1013187 | ENA
Project description: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 co-existence with stem cells making it difficult to culture Panth cells alone in vitro. Using a simplied 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 1,300 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 3,600 cells. This work is the first proteomics study of intestinal tissue enriched with Paneth cells. The simplied 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.
2022-10-12 | PXD034143 | Pride
Project description:Paneth cells are the primary, and possibly the sole, source of lysozyme in the intestinal lumen. Mice lacking the Paneth cell lysozyme gene, Lyz1, had diminished NLR signaling and basal inflammation, and were further protected from experimental colitis. Protection depended on an enhanced goblet and tuft cell program that was driven by IL13-IL4Ra-Stat6 signaling and required an expansion of lysozyme-sensitive mucolytic bacteria. Forced ectopic lysozyme production in colonic epithelium suppressed these bacteria and exacerbated colitis. Single cell RNA-seq of Lyz1 KO lamina propria revealed an activated ILC2 profile towards cytokine production. One lysozymesensitive species, Ruminococcus gnavus , when processed by lysozyme, induced a pro-inflammatory response, while non-processed R. gnavus stimulated IL13 production in lymphocytes. Consistent with a role of lysozyme for cell-wall processing in the inflammatory response, Lyz1 KO microbiota was anti-colitogenic in lysozymedeficient hosts but colitogenic in lysozyme-sufficient hosts. Thus, Paneth cell lysozyme regulates inflammatory tone by modulating mucosal response to specific bacterial groups.
2020-08-19 | GSE151151 | GEO
Project description:The impact of Mll1 removal on the intestinal stem cells and its direct effect on neighbouring Paneth cells was evaluated in sorted intestinal stem and Paneth cells from Mll1FC/+; Lgr5-eGFP-CreERT2/+ (control) and Mll1FC/FC; Lgr5-eGFP-CreERT2/+ (knockout) mice, 4 and 10 days after tamoxifen-induced mutagenesis. Using 75-base-pair reads, 30 million reads per sample with comparable unique mapped reads for stem (70-77%) and Paneth (60-76%) cells were obtained. To analyze differentially expressed genes, we applied DESeq2 analysis to the RNA-seq dataset. Analysis by DAVID and GSEA at a false discovery rate (FDR) of 5% was conducted.The stem cell transcriptome revealed that Mll1 knockout stem cells exhibited a decreased expression of several transcription factors and stem cell genes. Additionally, Mll1 ablation in stem cells had an impact on Paneth cells. Downregulation of Paneth cell specific markers indicated a loss of Paneth cell identity.
2021-11-10 | GSE157285 | GEO
Project description:The mammalian intestine is one of the most rapidly self-renewing tissues, driven by actively cycling stem cells residing at the crypt bottom . Together with stromal cells, Paneth cells form a major element of the niche microenvironment that provides various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. With 19 family members, different Wnt ligands can selectively activate βcatenin dependent (canonical) or independent (non-canonical) signaling. Here, we report that Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and non-canonical Wnt (Wnt/PCP) signaling, and their function is required for Paneth cell progenitor differentiation. We found that Daam1/2 interacts with the Wnt antagonist Rnf43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing Rnf43-dependent endo-lysosomal degradation of the ubiquitinated Wnt receptor, Frizzled (Fzd). Moreover, single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion, as a result of defective Wnt/PCP signaling. Taken together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and non-canonical Wnt signaling, the regulation of which is fundamental for specifying an adequate number of Paneth cells while maintaining intestinal stem cell homeostasis.
2023-08-25 | GSE239710 | GEO
Project description:Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5+ stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn's disease. Kaplan-Meier survival analysis of CRC patients revealed that low PRKCI levels correlated with significantly worse patient survival. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis.
2017-08-23 | GSE84118 | GEO
Project description:The impact of removal of Mll1 in intestinal Paneth cells expressing an constitutively active form of beta-catenin (beta-cateninGOF) was analysed in 4 pairs of sorted Paneth cells of Lgr5-CreERT2; beta-cateninGOF;Mll1+/- (control) and Lgr5-CreERT2; beta-cateninGOF;Mll1-/- (knockout) mice at 10 days after tamoxifen-induced mutagenesis. Using 75-base-pair reads, around 30 million reads per sample with comparable unique mapped reads (52-93%) were obtained. To analyze differentially expressed genes, we applied DESeq2 analysis to the RNA-seq dataset. Differentially expressed genes in beta-cateninGOF; Mll1-/- versus beta-cateninGOF; Mll1+/- Paneth cells showed both up- and downregulation of genes at a false discovery rate (FDR) of 10%. This included a global increase in the expression of goblet cell-specific genes. Downregulated genes included specific markers of Paneth cells, indicating that ablation of Mll1 in Paneth cells shifted their identity towards a mixed Paneth-goblet cell fate.
2022-01-08 | GSE177047 | GEO
Project description:Here, we developed an optimal system for culturing human small intestinal organoids (hSIOs) that recapitulate the structural and functional complexity of the intestinal crypt in vitro, including mature Paneth cells. With this model, we found that IL-22 is required for the differentiation of human Paneth cells. Rather than STAT3, the PI3K-mTORC1 axis, downstream of IL-22, mediates Paneth cell differentiation programs. CD-associated variants of the IL-22 receptor (IL10RB) were introduced in our system, resulting in the abolishment of Paneth cells in hSIOs. Moreover, our data demonstrated that long-term IL-22 exposure inhibited the growth of hSIOs, challenging the current perception of IL-22 in promoting intestinal regeneration, but rather in reducing cell viability. As a proof-of-principle, our study demonstrates that this optimal culture system for hSIOs has great potential for modelling human intestinal physiology and pathophysiology.
2022-08-23 | GSE189423 | GEO
Project description:This study delineated how small intestinal resident microflora impact gene expression in Paneth cells. Keywords: functional genomics; transcriptional profiling
2006-06-28 | GSE5156 | GEO