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

doi:10.15252/embr.202256030

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 journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Article number	e56030
Journal	EMBO Reports
Volume	24
Issue number	7
DOIs	https://doi.org/10.15252/embr.202256030
State	Published - Jul 5 2023

Funding

We thank William Muller (Northwestern University) and Bona Jabri (University of Chicago) for helpful advice. mice were kindly provided by Dr. Ralf Adams at the Max Planck Institute for Molecular Biomedicine, Germany. Single‐cell RNA‐seq experiments were performed at the NUSeq Core Facility at Northwestern University. This work was supported by the NIH (R01HL144129 and R01HL159976 to TK; R01DK117296 to WY and VS). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Cdh5‐Cre ERT2 We thank William Muller (Northwestern University) and Bona Jabri (University of Chicago) for helpful advice. Cdh5-CreERT2 mice were kindly provided by Dr. Ralf Adams at the Max Planck Institute for Molecular Biomedicine, Germany. Single-cell RNA-seq experiments were performed at the NUSeq Core Facility at Northwestern University. This work was supported by the NIH (R01HL144129 and R01HL159976 to TK; R01DK117296 to WY and VS). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.

Keywords

CXCL12
Wnt/R-spondin
intestinal regeneration
ischemia
paracrine signaling

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

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10.15252/embr.202256030

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title = "Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia–reperfusion injury",

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.",

keywords = "CXCL12, Wnt/R-spondin, intestinal regeneration, ischemia, paracrine signaling",

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

note = "Funding Information: We thank William Muller (Northwestern University) and Bona Jabri (University of Chicago) for helpful advice. mice were kindly provided by Dr. Ralf Adams at the Max Planck Institute for Molecular Biomedicine, Germany. Single‐cell RNA‐seq experiments were performed at the NUSeq Core Facility at Northwestern University. This work was supported by the NIH (R01HL144129 and R01HL159976 to TK; R01DK117296 to WY and VS). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Cdh5‐Cre ERT2 Funding Information: We thank William Muller (Northwestern University) and Bona Jabri (University of Chicago) for helpful advice. Cdh5-CreERT2 mice were kindly provided by Dr. Ralf Adams at the Max Planck Institute for Molecular Biomedicine, Germany. Single-cell RNA-seq experiments were performed at the NUSeq Core Facility at Northwestern University. This work was supported by the NIH (R01HL144129 and R01HL159976 to TK; R01DK117296 to WY and VS). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2023 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2023",

month = jul,

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doi = "10.15252/embr.202256030",

language = "English (US)",

volume = "24",

journal = "EMBO Reports",

issn = "1469-221X",

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T1 - Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia–reperfusion injury

AU - Tan, Can

AU - Norden, Pieter R.

AU - Yu, Wei

AU - Liu, Ting

AU - Ujiie, Naoto

AU - Lee, Sun Kyong

AU - Yan, Xiaocai

AU - Dyakiv, Yaryna

AU - Aoto, Kazushi

AU - Ortega, Sagrario

AU - De Plaen, Isabelle G.

AU - Sampath, Venkatesh

AU - Kume, Tsutomu

N1 - Funding Information: We thank William Muller (Northwestern University) and Bona Jabri (University of Chicago) for helpful advice. mice were kindly provided by Dr. Ralf Adams at the Max Planck Institute for Molecular Biomedicine, Germany. Single‐cell RNA‐seq experiments were performed at the NUSeq Core Facility at Northwestern University. This work was supported by the NIH (R01HL144129 and R01HL159976 to TK; R01DK117296 to WY and VS). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Cdh5‐Cre ERT2 Funding Information: We thank William Muller (Northwestern University) and Bona Jabri (University of Chicago) for helpful advice. Cdh5-CreERT2 mice were kindly provided by Dr. Ralf Adams at the Max Planck Institute for Molecular Biomedicine, Germany. Single-cell RNA-seq experiments were performed at the NUSeq Core Facility at Northwestern University. This work was supported by the NIH (R01HL144129 and R01HL159976 to TK; R01DK117296 to WY and VS). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Publisher Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2023/7/5

Y1 - 2023/7/5

N2 - 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.

AB - 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.

KW - CXCL12

KW - Wnt/R-spondin

KW - intestinal regeneration

KW - ischemia

KW - paracrine signaling

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SN - 1469-221X

VL - 24

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ER -

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

Abstract

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Keywords

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