Research ArticleVASCULAR BIOLOGY

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling

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Sci. Signal.  03 Oct 2017:
Vol. 10, Issue 499, eaal2987
DOI: 10.1126/scisignal.aal2987

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Moving lymphatic endothelial cells about

Lymphatic vessels return fluid and immune cells from peripheral tissues back to the circulation. The growth of new lymphatic vessels and their remodeling are critical for clearing infection and for metastasis of many cancer subtypes. Williams et al. compared the results of their functional siRNA screens with previously published mRNA data sets to identify genes that regulated lymphatic endothelial cell migration, a process critical for lymphatic vessel growth and remodeling, and genes that functioned in both lymphatic and blood endothelial cell migration. One of the top candidates to emerge from these analyses, the glycan-binding protein Galectin-1 not only promoted lymphatic vessel growth but also was important for maintaining lymphatic endothelial cell identity. Further analyses of the authors’ results may reveal lymphatic vessel–associated proteins that could be targeted to prevent edema, improve infection outcomes, or limit metastasis.

Abstract

Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity–induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that LGALS1, which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels.

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