Impaired Wnt/\u03b2-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis

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

doi: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.

Highlights

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in neonates and a major cause of death in preterm infants[1,2]
These findings were validated in human preterm infants by studying the intestinal epithelium during acute active NEC
We showed that provision of an exogenous source of Wnt, activated Intestinal stem cell (ISC) to promote epithelial cell proliferation, differentiation, and repair of the intestinal epithelial injury (Fig. 5)

Summary

Introduction

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in neonates and a major cause of death in preterm infants[1,2]. Despite recent advances in neonatal care, mortality from NEC remains high at 15–30%, demonstrating the need for innovative treatment strategies[3]. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)[7]. These cells are localized within the intestinal crypts and are critical for damage-induced intestinal regeneration[8]. ISC depletion correlates with severe gut damage during NEC development[10], and dietary agents that promote ISC expansion can ameliorate NEC severity[11]. These findings highlight a critical link between ISC function and intestinal repair processes

Methods

Results

Conclusion