Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis
Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis
复制标题
坏死性小肠结肠炎时Wnt/β-catenin通路受损导致肠再生功能障碍
DOI：
10.1038/s41419-019-1987-1
复制
发表时间：
2019-10-03
影响因子：
9
通讯作者：
Pierro, Agostino
中科院分区：
文献类型：
--
作者：
Li, Bo;Lee, Carol;Pierro, Agostino
坏死性小肠结肠炎（NEC）是一种以急性肠道损伤为特征的新生儿疾病。肠干细胞（ISC）更新是肠道再生所必需的，以应对急性损伤。Wnt/β-catenin通路对于肠道更新和ISC维持是必不可少的。我们发现，ISC表达，Wnt活性和肠再生都在实验性NEC小鼠和急性活动性NEC婴儿中降低。此外，来自小鼠和人的NEC损伤的肠的肠类器官未能维持增殖并呈现更多的分化。给予Wnt 7 b可逆转这些变化并促进肠道类器官的生长。此外，外源性Wnt 7 b的给药挽救了肠损伤，恢复了ISC，并重建了NEC小鼠的肠上皮稳态。我们的研究结果表明，在NEC期间，Wnt/β-catenin信号转导减少，ISC活性受损，肠再生缺陷。Wnt的管理导致维持肠上皮细胞的稳态和避免NEC肠损伤。
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/beta-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/beta-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.