Study: FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure 9149 cells

Using single-cell RNA sequencing, we established an atlas of adult mouse mesenteric lymphatic endothelial cell subtypes.

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. In mice, 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 a 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. 

Contributed by: Alejandra González-Loyola, Esther Bovay, Jaeryung, 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 and Tatiana V. Petrova, 2021. Science Advances, Vol 7, Issue 29, DOI: 10.1126/sciadv.abf4335