FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure

Alejandra González-Loyola, Esther Bovay, Jaeryung Kim, Tania Wyss Lozano, Amélie Sabine, Francois Renevey, Silvia Arroz-Madeira, Alexis Rapin, Tomasz P. Wypych, Giorgia Rota, Stephan Durot, Dominique Velin, Benjamin Marsland, Greta Guarda, Mauro Delorenzi, Nicola Zamboni, Sanjiv A. Luther, Tatiana V. Petrova

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

Abstract

The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor Foxc2 in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. Foxc2 loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2. Commensal microbiota depletion dampened systemic pro-inflammatory cytokine levels, corrected intestinal lymphatic dysfunction, and improved survival. Foxc2 loss skewed the specialization of lymphatic endothelial subsets, leading to populations with mixed, pro-fibrotic identities and to emergence of lymph node-like endothelial cells. Our study uncovers a cross-talk between lymphatic vascular function and commensal microbiota, provides single-cell atlas of lymphatic endothelial subtypes, and reveals organ-specific and systemic effects of dysfunctional lymphatics. These effects potentially contribute to the pathogenesis of diseases, such as inflammatory bowel disease, cancer, or lymphedema.

Original languageEnglish
Article numbereabf4335
Number of pages21
JournalScience Advances
Volume7
Issue number29
DOIs
Publication statusPublished - Jul 2021

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