Endoplasmic reticulum stress negatively regulates intestinal stem cells mediated by activation of GRP78/ATF6/CHOP signal

Abstract Impairment of intestinal stem cells (ISCs) is closely associated with various intestinal diseases. Endoplasmic reticulum stress (ERS) and cellular apoptosis are widely recognized as important factors during the development of intestinal diseases. However, whether ERS negatively affects numbers and differentiation ability of ISCs remains unknown. In the present study, tunicamycin (TM) was utilized to induce ERS in the mouse intestine to further investigate the underlying mechanisms on ERS-induced intestinal damage. The results showed that mice treated with TM at a dose of 1 mg/kg resulted in a significant reduction in body weight, shortening of the intestinal villi, deepening of the intestinal crypts and disruption of the intestinal barrier when compared to the control group. The numbers of ISCs, endocrine cells, goblet cells in the small intestine were significantly reduced after TM exposure. TM treatment decreased cellular proliferation and increased apoptosis in the cryptic area. Especially, Immunofluorescence double staining showed that ERS significantly increased expression of GRP78 and cellular apoptosis in ISCs. Further evidence indicated that GRP78/ATF6/CHOP signal pathway was activated while p44/42 MAPK signaling was significantly inhibited after TM treatment. These data suggest that TM-induced ERS reduces ISC numbers and diminishes ISC differentiation capacity through inhibiting cellular proliferation and increasing apoptosis.