Document Type

Article

Publication Date

7-5-2023

Identifier

DOI: 10.15252/embr.202256030; PMCID: PMC10328078

Abstract

Intestinal ischemia underlies several clinical conditions and can result in the loss of the intestinal mucosal barrier. Ischemia-induced damage to the intestinal epithelium is repaired by stimulation of intestinal stem cells (ISCs), and paracrine signaling from the vascular niche regulates intestinal regeneration. Here, we identify FOXC1 and FOXC2 as essential regulators of paracrine signaling in intestinal regeneration after ischemia-reperfusion (I/R) injury. Vascular endothelial cell (EC)- and lymphatic EC (LEC)-specific deletions of Foxc1, Foxc2, or both in mice worsen I/R-induced intestinal damage by causing defects in vascular regrowth, expression of chemokine CXCL12 and Wnt activator R-spondin 3 (RSPO3) in blood ECs (BECs) and LECs, respectively, and activation of Wnt signaling in ISCs. Both FOXC1 and FOXC2 directly bind to regulatory elements of the CXCL12 and RSPO3 loci in BECs and LECs, respectively. Treatment with CXCL12 and RSPO3 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.

Journal Title

EMBO reports

Volume

24

Issue

7

First Page

56030

Last Page

56030

MeSH Keywords

Mice; Animals; Intestines; Endothelial Cells; Wnt Signaling Pathway; Intestinal Mucosa; Reperfusion Injury

Keywords

CXCL12; Wnt/R-spondin; intestinal regeneration; ischemia; paracrine signaling

Comments

Grant support

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://www.embopress.org/doi/full/10.15252/embr.202256030

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