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

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.

• Authors: Steven P Williams, Adam F Odell, Tara Karnezis, Rae H Farnsworth, Cathryn M Gould, Jason Li, Sophie Paquet-Fifield, Nicole C Harris, Anne Walter, Julia L Gregory, Sara F Lamont, Ruofei Liu, Elena A Takano, Cameron J Nowell, Neil I Bower, Daniel Resnick, Gordon K Smyth, Leigh Coultas, Benjamin M Hogan, Stephen B Fox, Scott N Mueller, Kaylene J Simpson, Marc G Achen, Steven A Stacker
• Journal: Science signaling (Sci Signal) Vol. 10 Issue 499 (Oct 03 2017) ISSN: 1937-9145 [Electronic] United States
• PMID: 28974649 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Galectin 1
• LGALS1 protein, human

Topics

• Cell Movement (physiology)
• Endothelial Cells (cytology, metabolism)
• Galectin 1 (genetics, metabolism)
• Genome-Wide Association Study
• Humans
• Signal Transduction (physiology)