Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis

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Abstract

Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/β-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/β-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury.

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Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration.

Ciara Metcalfe, Noelyn Kljavin, Ryan Ybarra … (2014)

The intestinal epithelium continually self-renews and can rapidly regenerate after damage. Lgr5 marks mitotically active intestinal stem cells (ISCs). Importantly, intestinal homeostasis can be maintained after depletion of Lgr5(+) cells due to the activation of Lgr5(-) reserve ISCs. The Lgr5(-) ISC populations are thought to play a similar role during intestinal regeneration following radiation-induced damage. We tested this regeneration hypothesis by combining depletion of Lgr5(+) ISCs with radiation exposure. In contrast to the negligible effect of Lgr5(+) ISC loss during homeostasis, depletion of Lgr5(+) cells during radiation-induced damage and subsequent repair caused catastrophic crypt loss and deterioration of crypt-villus architecture. Interestingly though, we found that crypts deficient for Lgr5(+) cells are competent to undergo hyperplasia upon loss of Apc. These data argue that Lgr5(-) reserve stem cells are radiosensitive and that Lgr5(+) cells are crucial for robust intestinal regeneration following radiation exposure but are dispensable for premalignant hyperproliferation. Copyright © 2014 Elsevier Inc. All rights reserved.

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Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury.

Hiroyuki Miyoshi, Rieko Ajima, Christine Luo … (2012)

Reestablishing homeostasis after tissue damage depends on the proper organization of stem cells and their progeny, though the repair mechanisms are unclear. The mammalian intestinal epithelium is well suited to approach this problem, as it is composed of well-delineated units called crypts of Lieberkühn. We found that Wnt5a, a noncanonical Wnt ligand, was required for crypt regeneration after injury in mice. Unlike controls, Wnt5a-deficient mice maintained an expanded population of proliferative epithelial cells in the wound. We used an in vitro system to enrich for intestinal epithelial stem cells to discover that Wnt5a inhibited proliferation of these cells. Surprisingly, the effects of Wnt5a were mediated by activation of transforming growth factor-β (TGF-β) signaling. These findings suggest a Wnt5a-dependent mechanism for forming new crypt units to reestablish homeostasis.

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Microenvironmental regulation of stem cells in intestinal homeostasis and cancer.

Jan Paul Medema, Louis Vermeulen (2011)

The identification of intestinal stem cells as well as their malignant counterparts, colon cancer stem cells, has undergone rapid development in recent years. Under physiological conditions, intestinal homeostasis is a carefully balanced and efficient interplay between stem cells, their progeny and the microenvironment. These interactions regulate the astonishingly rapid renewal of the intestinal epithelial layer, which consequently puts us at serious risk of developing cancer. Here we highlight the microenvironment-derived signals that regulate stem-cell fate and epithelial differentiation. As our understanding of normal intestinal crypt homeostasis grows, these developments may point towards new insights into the origin of cancer and the maintenance and regulation of cancer stem cells.

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Author and article information

Contributors

Agostino Pierro: +1 416-813-7340 , agostino.pierro@sickkids.ca

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 3 October 2019

Publication date PMC-release: 3 October 2019

Publication date Collection: October 2019

Volume: 10

Issue: 10

Electronic Location Identifier: 743

Affiliations

[1 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Translational Medicine Program, , The Hospital for Sick Children, ; Toronto, ON M5G 1X8 Canada

[2 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Division of General and Thoracic Surgery, , The Hospital for Sick Children, ; Toronto, ON M5G 1X8 Canada

[3 ]ISNI 0000 0004 0407 2968, GRID grid.411333.7, Department of Pediatric Surgery, , Children’s Hospital of Fudan University, ; 201102 Shanghai, China

[4 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Cell Biology Program, , The Hospital for Sick Children, ; Toronto, ON M5G 1X8 Canada

[5 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Division of Pathology, , The Hospital for Sick Children, ; Toronto, ON M5G 1X8 Canada

[6 ]ISNI 0000000121901201, GRID grid.83440.3b, UCL Great Ormond Street Institute of Child Health, ; London, WC1N 1EH UK

[7 ]GRID grid.448594.0, Biology Department, , Burman University, ; Lacombe, AB T4L 2E5 Canada

[8 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Molecular Genetics, , University of Toronto, ; Toronto, ON M5S 1A8 Canada

[9 ]GRID grid.423576.1, Heart & Stroke Richard Lewar Centre of Excellence, ; Toronto, ON M5S 3H2 Canada

[10 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Division of Gastroenterology, Hepatology and Nutrition, , The Hospital for Sick Children, ; Toronto, ON M5G 1X8 Canada

[11 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Faculty of Medicine, Department of Laboratory Medicine and Pathobiology, , University of Toronto, ; Toronto, ON M5S 1A8 Canada

[12 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Faculty of Dentistry, , University of Toronto, ; Toronto, ON M5G 1G6 Canada

[13 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Developmental and Stem Cell Biology Program, , The Hospital for Sick Children, ; Toronto, ON M5G 1X8 Canada

[14 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Surgery, , University of Toronto, ; Toronto, ON M5S 1A8 Canada

Author information

Bo Li http://orcid.org/0000-0002-8298-8344

Kathene C. Johnson-Henry http://orcid.org/0000-0002-6046-550X

Simon Eaton http://orcid.org/0000-0003-0892-9204

Article

Publisher ID: 1987

DOI: 10.1038/s41419-019-1987-1

PMC ID: 6776513

PubMed ID: 31582728

SO-VID: fe60f41c-b062-46fc-93bf-0fa3e4f87453

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 5 June 2019

Date accepted : 17 September 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100006126, Hospital for Sick Children (SickKids);

Award ID: Robert M. Filler Chair of Surgery

Award ID: Restracomp Fellowship

Award ID: Operational Funds

Award Recipient : Bo Li Paul Delgado-Olguin Agostino Pierro

Funded by: FundRef https://doi.org/10.13039/501100000024, Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada);

Award ID: Foundation Grant 353857

Award ID: PJT-149046

Award Recipient : Paul Delgado-Olguin Agostino Pierro

Funded by: FundRef https://doi.org/10.13039/100005627, Thrasher Research Fund;

Award ID: Early Career Award Program

Award Recipient : Bo Li

Funded by: FundRef https://doi.org/10.13039/501100000272, DH | National Institute for Health Research (NIHR);

Funded by: FundRef https://doi.org/10.13039/501100002790, Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology);

Award ID: grant 500865

Award Recipient : Paul Delgado-Olguin

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ScienceOpen disciplines: Cell biology

Keywords: intestinal diseases,preclinical research

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: intestinal diseases, preclinical research

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Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 28

Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration.

Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury.

Microenvironmental regulation of stem cells in intestinal homeostasis and cancer.

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