The Jagged-1/Notch-1/Hes-1 Pathway Is Involved in Intestinal Adaptation in a Massive Small Bowel Resection Rat Model

Abstract

Notch signaling is required for the maintenance of intestinal epithelial proliferation. Dysfunction of this signaling pathway is associated with the loss of proliferated crypt epithelial cells. The aim of this study was to investigate the role of Notch signaling in small bowel resection (SBR)-associated crypt epithelial cell proliferation. Male Sprague-Dawley rats were subjected to sham operation (bowel transection and reanastomosis) or 70% mid-SBR. Intestinal tissue samples were collected at 0.5, 1, 6, 12, 24, 72, and 168 h after operation. The expression of Notch pathway mRNAs and proteins was analyzed using RT-PCR and Western blot. The expression of the Notch pathway proteins Jagged-1, NICD and Hes-1 was also determined through immunohistochemical staining using day 3 postoperative intestinal tissues. The degree of crypt epithelial cell proliferation was evaluated using the immunohistochemical staining of proliferating cell nuclear antigen (PCNA). Furthermore, IEC-6 cells were used to examine the function of the Jagged-1 signaling system. SBR led to increased crypt epithelial cell proliferation and increased expression of Jagged-1 and Hes-1 mRNA and protein along with cleaved Notch-1. Immunohistochemical staining showed that Jagged-1, cleaved Notch-1 and Hes-1 colocalized in the same proliferated crypt epithelial cell population. Recombinant Jagged-1 significantly stimulated the proliferation of IEC-6 cells. Transient upregulation of Jagged-2 expression was found 1 h after SBR, and it was accompanied by cleaved Notch-1 and Hes-1 upregulation. The Jagged-1/Notch-1/Hes-1 signaling pathway is involved in intestinal adaptation through increasing crypt epithelial cell proliferation.