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Gut lymphatics functionally adapt to the region they drain and are altered by helminths [NI-Sv_5-8_dpi_Mucosa_RNAseq]

ABSTRACT: Tissue lymphatics are crucial for fluid homeostasis and immunosurveillance. We asked whether the lymphatics are adapted to the organ in which they reside, such as along the gut. Duodenal lymphatic capillaries (lacteals) displayed the mot discontinuous tight junction composition versus lacteals at other sites, resulting in a dependence on duodenal lacteals for rapid dietary lipid uptake. Duodenal helminths abrogated these features. RNAseq of LECs and the mucosa along the intestine revealed that LEC transcriptomes matched the functional profile of the local mucosa. Helminth infection reverses key duodenal signatures like lipid metabolism and immune activation, instead triggering lymphangiogenic and mucosal antimicrobial responses. We identified a putative VEGFR2/3 signaling gradient that may explain differences in tight junction along the small intestine at homeostasis. Inflammation-induced lymphangiogenesis and decreased fat exposure likely underlie duodenal lymphatic impermeability upon helminth infection, while microbial depletion acted additively on lymphatic restructuring. Our study provides molecular insights into lymphatic function along the intestine and stages lymphatic permeability as subject to dynamic regulation by environmental queues.

ORGANISM(S): Mus musculus

PROVIDER: GSE271711 | GEO | 2024/07/08

REPOSITORIES: GEO

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Project description:Invasion of lymphatic vessels is a key step in the metastasis of primary tumour cells to draining lymph nodes. Recent evidence indicates that such metastasis can be facilitated by tumour lymphangiogenesis, although it remains unclear whether this is a consequence of increased lymphatic vessel numbers or alteration in the properties of the vessels themselves. Here we have addressed this important question by comparing the RNA profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T-241/VEGF-C metastatic fibrosarcoma. Our findings reveal significant changes in the expression of some 792 genes in tumour lymphatics (â?¥ 2 fold up/downregulation, p â?¤ 0.05), involving particularly transcripts associated with junctional adhesion, immunomodulation, extracellular matrix and vessel growth/patterning, several of which we have confirmed by RT-PCR and/or immunohistochemistry. Interestingly, this altered phenotype could not be attributed solely to VEGF-C induced lymphoproliferation, as no similar change in gene expression was reported when human LEC were cultured with VEGF-C in vitro. Moreover, we show that a key protein upregulated in the mouse model, namely the tight junction protein Endothelial Cell Specific Adhesion Molecule (ESAM), is similarly upregulated in tumour lymphatic vessels from 2/2 patients with head and neck squamous cell carcinoma and 4/4 patients with aggressive bladder carcinoma. These findings demonstrate a previously unrecognized influence of tumour environment on lymphatic gene expression and identify candidate tumour specific vessel markers that may prove valuable for either prognosis or therapy. Experiment Overall Design: Here we have investigated the invasion of lymphatic vessels as a key step in the metastasis of primary tumour cells to draining lymph nodes by comparing the gene expression profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T241/VEGF-C/GFP metastatic fibrosarcoma. Three biological replicates were analyzed from each group.

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Gut lymphatics functionally adapt to the region they drain and are altered by helminths [NI-Sv_5-8_dpi_Mucosa_RNAseq]

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