JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation

The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response. [Display omitted] •Reserve intestinal stem cells (r-ISCs) enter the cell cycle following inflammation•Activated r-ISCs proliferate and contribute to intestinal regeneration•Cytokine-stimulated JAK/STAT-1 signaling is required for r-ISC activation Richmond et al. demonstrate that, following intestinal inflammatory injury, reserve intestinal stem cells (r-ISCs) exit quiescence and contribute to intestinal regeneration. In contrast, crypt base columnar ISCs undergo apoptosis and show a reduced lineage contribution in the immediate recovery period. JAK/STAT-1 signaling is required for r-ISC activation during the early recovery period following inflammatory injury.