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

Can Tan, Pieter R. Norden, Wei Yu, Ting Liu, Naoto Ujiie, Sun Kyong Lee, Xiaocai Yan, Yaryna Dyakiv, Kazushi Aoto, Sagrario Ortega, Isabelle G. De Plaen, Venkatesh Sampath, Tsutomu Kume*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Article numbere56030
JournalEMBO Reports
Issue number7
StatePublished - Jul 5 2023


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

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry


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