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MiRNA expression profiling of intestinal epithelial cell-derived extracellular vesicles from mice following Paneth cell ablation by dithizone

ABSTRACT: Paneth cells, critical sentinels of the innate immune system within the intestinal epithelium, play a vital role in maintaining intestinal homeostasis and defending against pathogens. Their dysfunction is implicated in the pathogenesis of sepsis. However, the specific mechanisms by which Paneth cells communicate with and regulate the surrounding intestinal microenvironment, particularly via extracellular vesicles (EVs), remain poorly understood. This study aims to characterize the global miRNA expression profile of intestinal epithelial cell-derived EVs (IEC-EVs) in a mouse model of acute Paneth cell loss, to identify key intercellular signaling molecules that may mediate intestinal barrier response to injury. We employed a well-established model of Paneth cell ablation by a single intraperitoneal injection of dithizone in C57BL/6 mice. Control mice received a vehicle solution. Intestinal epithelial cells were isolated six hours post-injection, and IEC-EVs were subsequently purified from these cells. Small RNA from the purified IEC-EVs was extracted and subjected to next-generation sequencing to comprehensively profile the miRNA cargo. Our comparative analysis reveals a distinct set of miRNAs that are differentially expressed in IEC-EVs following Paneth cell ablation. These candidate miRNAs are predicted to target signaling pathways crucial for epithelial cell proliferation, apoptosis, and inflammatory responses. We hypothesize that the alteration of the miRNA landscape in IEC-EVs represents a novel mechanism of intercellular communication that orchestrates the intestinal epithelial response to damage. This dataset provides the comprehensive resource of miRNA expression in IEC-EVs under conditions of Paneth cell deficiency. The findings are expected to elucidate novel pathways in intestinal pathophysiology and may identify potential miRNA biomarkers or therapeutic targets for conditions involving intestinal barrier dysfunction, such as sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE311914 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Crohn’s disease (CD) is associated with multiple Paneth cell dysfunctions such as altered antimicrobial secretion that relies on autophagy - an essential process controlling the turnover of cellular components. Genome-wide association studies have linked CD to mutations in the ATG16l1 gene, encoding an important component of the autophagy machinery. Patients carrying the ATG16l1 CD risk allele have Paneth cell abnormalities, as reproduced in Atg16l1-deficient mouse models. However, the direct effect of the ATG16L1-deficiency and autophagy-impairment in Paneth cells has not been analysed in detail. To investigate this, we generated a mouse model lacking ATG16L1 specifically in intestinal epithelial cells (Atg16l1△IEC) making these cells impaired in autophagy. Using a 3D small intestinal organoid culture model, which we enriched for Paneth cells and compared the proteomic profiles of organoids derived from the wild-type (WT) and the Atg16l1△IEC mice. We used an integrated computational approach combining protein-protein interaction networks, list of proteins potentially targeted by autophagy and functional information on the proteins with altered protein levels to identify the mechanistic link between autophagy-impairment and disrupted cellular process. 198 (70%) of the 284 altered proteins were more abundant in autophagy-impaired organoids than WT organoids that could be due to a reduced protein turnover. Combining the proteomic dataset with the potential target proteins of selective autophagy proteins revealed that 116 (41%) of the differentially abundant proteins could rely on autophagy-mediated turnover. Taken together, our results suggest that proteins with increased levels in autophagy-impaired background require an autophagy-mediated turnover mechanism, and that their altered levels in CD could affect key cellular processes. Consequently, we pointed out the importance of autophagy in controlling the turnover of proteins relevant in key Paneth cell functions such as exocytosis, apoptosis and DNA damage repair. Our study unravels autophagy-dependent cellular processes of Paneth cells that not directly relies on the autophagy process, rather than a selective protein turnover mechanism. The identified proteins and processes open new avenues for targeted, cell type-specific therapeutic interventions in CD.

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MiRNA expression profiling of intestinal epithelial cell-derived extracellular vesicles from mice following Paneth cell ablation by dithizone

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