Condensin upregulation induces intestinal stem cell senescence, driving cell death and increased intestinal permeability

Abstract

Summary Intestinal stem cell maintenance ensures the integrity of the continuously renewing intestinal barrier, promotes repair, and prevents immune cell activation in the underlying tissue. Intestinal barrier defects contribute to the development of Crohn’s disease (CD), a type of inflammatory bowel disease (IBD). We show that expression of subunits of the genome-organizing complexes, condensins, is upregulated in intestinal epithelial cells of patients with ileal CD. Using cultured intestinal epithelial cell lines and the in vivo model of Drosophila melanogaster, we show that overexpression of condensin proteins rearranges heterochromatin and induces senescence of intestinal stem cells, which leads to cell death in both stem and non-stem cells. In Drosophila, this increases intestinal permeability. These findings suggest that restriction of condensin expression maintains ileal stem cell homeostasis, providing support for future mechanistic exploration of pathologic roles for condensins and senescent stem cells in CD and other diseases involving intestinal barrier dysfunction.