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

Abstract

Intestinal ischemia induces mucosal damage while simultaneously activating intestinal stem cells (ISCs), which subsequently regenerate the damaged intestinal epithelium. However, whether angiocrine factors secreted from vascular endothelial cells (ECs) - blood and lymphatic ECs (BECs and LECs, respectively) – regulate ISC-mediated regeneration have yet to be elucidated. Here, we identify FOXC1 and FOXC2 as essential regulators of angiocrine signaling in regeneration of the small intestine after ischemia-reperfusion (I/R) injury. EC- and LEC-specific deletions of Foxc1, Foxc2, or both in mice augment I/R-induced intestinal damage by causing defects in vascular regrowth, expression of the chemokine CXCL12 and the Wnt activator R-spondin 3 in BECs and LECs, respectively, and activation of Wnt signaling in ISCs. Treatment with CXCL12 and R-spondin 3 rescues the I/R-induced intestinal damage in EC- and LEC-Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating angiocrine CXCL12 and Wnt signaling.

Molecular characterization of FOX factors and Wnt signalling interplay in human cancers

“…Moreover, FoxM1 has been shown to promote intestinal epithelial regeneration and was associated with tissue regeneration after injury [185]. Similarly, FOXC1 and FOXC2 were shown to act through the regulation of the Wnt signalling pathway to promote intestinal regeneration [186].…”

Neutrophil extracellular traps drive intestinal microvascular endothelial ferroptosis by impairing Fundc1-dependent mitophagy

“…The intestine, a crucial organ with a substantial blood supply, is susceptible to damage induced by ischemia, hypoxia, and reperfusion. Intestinal microvascular endothelial dysfunction is known to be one of the main causes of gut barrier damage in developing II/R injury [ 3 , 4 ]. At the molecular and cellular levels, increased oxidative stress subsequently causes swelling and vacuolization of endothelial cells, intercellular tight junction loss and hyperpermeability, neutrophil infiltration, and microthrombus formation in the microvasculature [ 3 , 5 ].…”

“…Intestinal microvascular endothelial dysfunction is known to be one of the main causes of gut barrier damage in developing II/R injury [ 3 , 4 ]. At the molecular and cellular levels, increased oxidative stress subsequently causes swelling and vacuolization of endothelial cells, intercellular tight junction loss and hyperpermeability, neutrophil infiltration, and microthrombus formation in the microvasculature [ 3 , 5 ]. Microvascular injury and dysfunction lead to gut barrier damage, which triggers a vicious cycle of aggravating II/R injury [ 6 ].…”