Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis
Open Access
- 3 October 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 10 (10), 1-11
- https://doi.org/10.1038/s41419-019-1987-1
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.Keywords
Funding Information
- Hospital for Sick Children (Robert M. Filler Chair of Surgery, Restracomp Fellowship, Operational Funds)
- Gouvernement du Canada | Canadian Institutes of Health Research (Foundation Grant 353857, PJT-149046)
- Thrasher Research Fund (Early Career Award Program)
- DH | National Institute for Health Research
- Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (grant 500865)
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