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

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.

Differential roles of neural crest- and endothelial-derived FOXC2 in trabecular meshwork and Schlemm’s Canal in glaucomatous pathology

“…Foxc2 is a critical regulator of early lymphatic development as well as lymphatic maturation, maintenance, and function (10, 11, 13, 14). Our linage tracing analysis demonstrated that Foxc2 + cell descendants contribute to the formation of the SC vasculature ( Figure 1 ) and our single cell RNA-seq analysis shows that Foxc2 was more highly expressed in the SC and lymphatic EC cluster compared to the other BEC clusters ( Figure 7F ).…”

“…Axenfeld-Rieger (AR) malformations refer to autosomal dominant developmental abnormalities of the anterior eye segment associated with mutations in the transcription factors paired-like homeodomain transcription factor 2 (PITX2) and forkhead box (FOX)C1 and often results in the progression of glaucomatous blindness (8). In contrast to mutations in FOXC1, FOXC2 mutations are predominately associated with lymphatic vascular dysfunction and the progression of the autosomal dominant lymphedemadistichiasis syndrome (9)(10)(11). However, during development both Foxc1 and Foxc2 share overlapping expression patterns and function cooperatively and complementary to one another in various aspects of tissue development, including blood and lymphatic vascular growth and maintenance (12)(13)(14).…”

Caspase‐8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice

“…It has been reported that LEC depletion in mice leads to rapid lethality due to intestine‐specific hemorrhages and sepsis (Jang et al , 2013 ). Furthermore, exposure of intestinal epithelial cells with lymph fluid in a mouse model of lymphangiectasia leads to increased barrier permeability (Gonzalez‐Loyola et al , 2021 ). Consistently, here we find that already in the initial steps of disease development in Casp8 ECko mice, Peyer’s Patches display altered lymphatic vessel structure and LEC death and lacteals in the villi are also affected.…”

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury

“…While our qPCR and scRNA-seq analyses show that expression levels of Foxc1 in intestinal ECs are higher than those of Foxc2 , the phenotypic differences between EC-(or LEC-) Foxc1 -KO and EC-(or LEC-) Foxc2 -KO mice are not particularly distinct. Although the reason(s) for the phenotypic similarities remains unclear, recent evidence indicates that Foxc2 is essential for the maintenance of intestinal LECs, and that treatment with antibiotics to deplete gut microbiota rescues the phenotype of LEC-specific adult Foxc2 mutant mice, including lymphatic dilation in the small intestine ( 56 ). Bacterial translocation occurs when the intestinal barrier is disrupted by I/R injury, and intestinal damage after I/R injury can be attenuated by pretreating the animals with an antibiotic cocktail to deplete gut commensal bacteria ( 36 ).…”