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bioRxiv · 10.1101/2022.03.03.482713

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

Tan, C.·Norden, P. R.·Liu, T.·Ujiie, N.·Yan, X.·Aoto, K.·Ortega, S.·De Plaen, I. G.·Kume, T.
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Abstract

Intestinal ischemia induces mucosal damage while simultaneously activating intestinal stem cells (ISCs), which subsequently regenerate the damaged intestinal epithelium. However, whether paracrine 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 paracrine 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 paracrine CXCL12 and Wnt signaling.

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Tan, C., Norden, P. R., Liu, T., Ujiie, N., Yan, X., Aoto, K., Ortega, S., De Plaen, I. G., Kume, T.. 2022-03-03. Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury. https://doi.org/10.1101/2022.03.03.482713

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