Diet can impact on gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown if and how the ISC niche responds to diet and influences ISC function. Here, we demonstrate that Lepr + mesenchymal cells (MCs) surrounding intestinal crypts sense diet change and provide a novel niche signal to maintain ISC and progenitor cell proliferation. The abundance of these MCs increases upon administration of a high-fat diet (HFD) but dramatically decreases upon fasting. Depletion of Lepr + MCs resulted in fewer intestinal stem/progenitor cells, compromised the architecture of crypt-villus axis and impaired intestinal regeneration. Furthermore, we showed that IGF1 secreted by Lepr + MCs is an important effector that promotes proliferation of ISCs and progenitor cells in the intestinal crypt. We conclude that Lepr + MCs sense diet alterations and, in turn, modulate intestinal stem/progenitor cell function via a stromal IGF1-epithelial IGF1R axis. These findings reveal that Lepr + MCs are important mediators linking systemic diet changes to local ISC function and might serve as a novel therapeutic target for gut diseases.
Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.
Background Exosomes are extensively reported to be strongly associated with many immunologic diseases, including Crohn disease (CD). Meanwhile, the dysfunction of macrophage activation has been proposed to be critical for the pathogenesis of CD. However, it is an unsettled issue whether serum exosomes from CD could activate macrophages and participate in its pathogenesis. Our study intended to clarify the role of CD-derived exosomes on macrophages to elucidate a novel mechanism and possible diagnostic and therapeutic strategies. Methods Serum exosomes were isolated and identified. Functional assays in vitro were performed on Raw264.7 macrophages, followed by exosomal microRNA (miRNA) profiling and bioinformatics analyses via high-throughput sequencing. In animal experiments, exosomes were intraperitoneally injected into dextran sulfate sodium–induced colitis. Results In vitro CD-derived exosomes induced proinflammatory cytokine expression and increased macrophage counts. Meanwhile, the intervention of exosomes from CD with epithelial cells led to increased permeability of the intestinal epithelial barrier. In vivo, CD-derived exosomes could circulate into the intestinal mucosa and significantly aggravate colitis. Furthermore, CD changed the miRNA profile of exosomes and further analysis revealed a differential expression of let-7b-5p. Mechanistically, the let-7b-5p/TLR4 pathway was recognized as a potential contributor to macrophage activation and inflammatory response. Furthermore, serum exosome–mediated let-7b-5p mimic delivery alleviated colitis significantly. Conclusions Our study indicated that serum exosomes can circulate into the intestinal mucosa to aggravate colitis by regulating macrophage activation and epithelial barrier function. In addition, CD showed altered exosomal miRNA profiles. Furthermore, serum exosome–mediated let-7b-5p-mimic delivery may significantly alleviate colitis, providing potential novel insight into an exosome-based strategy for the diagnosis and treatment of CD.
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