JAK/STAT signaling promotes the emergence of unique cell states in ulcerative colitis

The intestinal epithelium ensures uptake of vital nutrients and acts as a barrier between luminal contents and the underlying immune system. In inflammatory bowel diseases, such as ulcerative colitis (UC), this barrier is compromised, and patients experience debilitating symptoms. Here, we perform single-cell RNA profiling of epithelial cells and outline patterns of cell fate decisions in healthy individuals and UC patients. We demonstrate that patterns of hierarchical behavior are altered in UC patients and identify unique cellular states associated with Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation in ulcerated and non-ulcerated areas of the colonic epithelium. These transcriptional changes could be recapitulated in human colonic organoids, wherein cytokine-mediated activation of JAK/STAT led to the emergence of cell populations with augmented regenerative properties. Altogether, our findings indicate that intricate relationships between epithelial and cytokine signaling regulate cell fate during epithelial tissue regeneration in humans and have important implications for the understanding of UC biology. •Lineage-biased TA cells are the main source of homeostatic tissue renewal•Colonic ulcers have widespread consequences even at distant sites•Organoid cultures recapitulate in vivo regenerative cell types•Unique cell states are induced by cytokine-mediated JAK/STAT signaling We demonstrate that, in patients with UC, cytokine-induced JAK/STAT signaling is involved in the emergence of previously uncharacterized inflammation-associated (IA) cell states. Based on single-cell expression analysis from patient samples and analysis of genetically engineered human organoid lines, we propose that IA cells play a role in tissue regeneration.