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

Bo Li; Carol Lee; Marissa Cadete; Haitao Zhu; Yuhki Koike; Alison Hock; Richard Y Wu; Steven R Botts; Adam Minich; Mashriq Alganabi; Lijun Chi; Elke Zani-Ruttenstock; Hiromu Miyake; Yong Chen; Annika Mutanen; Bo Ngan; Kathene C Johnson-Henry; Paolo De Coppi; Simon Eaton; Pekka Määttänen; Paul Delgado-Olguin; Philip M Sherman; Augusto Zani; Agostino Pierro

doi:10.1038/s41419-019-1987-1

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

Cell Death Dis. 2019 Oct 3;10(10):743. doi: 10.1038/s41419-019-1987-1.

Authors

Bo Li^{1

2}, Carol Lee^{1

2}, Marissa Cadete^{1

2}, Haitao Zhu^{1

2

3}, Yuhki Koike^{1

2}, Alison Hock^{1

2}, Richard Y Wu⁴, Steven R Botts⁴, Adam Minich^{1

2}, Mashriq Alganabi^{1

2}, Lijun Chi¹, Elke Zani-Ruttenstock^{1

2}, Hiromu Miyake^{1

2}, Yong Chen^{1

2}, Annika Mutanen², Bo Ngan⁵, Kathene C Johnson-Henry⁴, Paolo De Coppi⁶, Simon Eaton⁶, Pekka Määttänen⁷, Paul Delgado-Olguin^{1

8

9}, Philip M Sherman^{3

10

11

12}, Augusto Zani^{2

13

14}, Agostino Pierro^{15

16

17}

Affiliations

¹ Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
² Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
³ Department of Pediatric Surgery, Children's Hospital of Fudan University, 201102, Shanghai, China.
⁴ Cell Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
⁵ Division of Pathology, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
⁶ UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
⁷ Biology Department, Burman University, Lacombe, AB, T4L 2E5, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁹ Heart & Stroke Richard Lewar Centre of Excellence, Toronto, ON, M5S 3H2, Canada.
¹⁰ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
¹¹ Faculty of Medicine, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹² Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1G6, Canada.
¹³ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
¹⁴ Department of Surgery, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁵ Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada. agostino.pierro@sickkids.ca.
¹⁶ Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada. agostino.pierro@sickkids.ca.
¹⁷ Department of Surgery, University of Toronto, Toronto, ON, M5S 1A8, Canada. agostino.pierro@sickkids.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Enterocolitis, Necrotizing / genetics
Enterocolitis, Necrotizing / physiopathology*
Epithelial Cells / drug effects
Epithelial Cells / metabolism
Gene Expression Regulation / drug effects
Humans
Intestines / drug effects
Intestines / pathology
Intestines / physiopathology*
Mice, Inbred C57BL
Models, Biological
Organoids / drug effects
Organoids / metabolism
Proto-Oncogene Proteins / administration & dosage
Proto-Oncogene Proteins / pharmacology
Regeneration / drug effects
Regeneration / physiology*
Stem Cells / drug effects
Stem Cells / metabolism
Survival Analysis
Wnt Proteins / administration & dosage
Wnt Proteins / pharmacology
Wnt Signaling Pathway* / drug effects
Wnt Signaling Pathway* / genetics

Substances

Proto-Oncogene Proteins
Wnt Proteins
Wnt7b protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding