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Atlas of lymphangiogenesis [scATAC-Seq]

ABSTRACT: During development, lymphatic vasculature forms as a second and distinct network that derives from embryonic blood vessels. Transdifferentiation of venous endothelial cells into specified lymphatic endothelial cells (LECs) is the first step in this process. Transdifferentiation and specification of LEC fate requires Prox1, but how Prox1 regulates transdifferentiation and differentiation is not fully understood. We present a single cell transcriptomic atlas of lymphangiogenesis spanning four key developmental stages that reveals new markers and functional regulators of lymphatic development. We extend this to comprehensively profile single cell transcriptomic and chromatin changes controlled by Prox1 using zygotic prox1a mutants, which form lymphatics that then dedifferentiate. Combining this with single cell analysis of Prox1-null, double prox1a/prox1b maternal zygotic mutants, we reveal in depth the role of Prox1 in control of LEC fate specification and differentiation. This resource reveals dual and progressive functions for Prox1, blocking blood vascular and hematopoietic fate while simultaneously up-regulating a small number of early acting genes that include tspan18a/b and lgals3a/b which are essential for lymphangiogenesis. This embryonic developmental resource will serve as a baseline to better understand both developmental and pathological lymphangiogenesis in the future. [Citations in sample metadata correspond to reference numbers in the associated publication.]

ORGANISM(S): Danio rerio

PROVIDER: GSE188340 | GEO | 2023/04/27

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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Atlas of lymphangiogenesis [scATAC-Seq]

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